Parasiticidal dihydroisoxazole compounds

ABSTRACT

Provided are dihydroisoxazole compounds I useful for controlling parasites both in animals and agriculture. Further provided are methods for controlling parasite infestations of an animal by administering an effective amount of a compound as described above, or a pharmaceutically acceptable salt thereof, to an animal, as well as formulations for controlling parasite infestations using the compounds described above or an acceptable salt thereof, and an acceptable carrier. Also provided are compounds and processes useful for making the dihydroisoxazole compounds. 
     
       
         
         
             
             
         
       
     
     wherein A is

Ectoparasites such as fleas, lice, flies, mosquitoes, ticks and mites,as well as endoparasites such as gastrointestinal tract nematodes,flukes, and filarids, are problematic for man and animal alike. Suchparasites seriously impact productivity in the domesticated animalindustry by reducing weight gain, causing poor quality hide, wool, andmeat, and in some cases resulting in death. Ecto- and endoparasites arealso responsible, in part, for the spread of disease and discomfort infood and companion animals. Ectoparasites in particular are known toharbor and transmit a variety of microbial pathogens, includingbacteria, viruses and protozoan parasites, many of which are pathogenicto humans, other warm-blooded mammals and birds. Diseases in whichectoparasites have been implicated include, but are not limited to,malaria, lymphatic- and blood-born filariasis, trachoma,trypanosomiasis, Leishmaniasis, Rocky Mountain Spotted Fever, LymeDisease, babesiosis, and food-borne illnesses due to Salmonella, E. coliand Campylobacter, for example.

The medical importance of parasiticide infestations has prompted thedevelopment of reagents capable of controlling such. Commonlyencountered methods to control parasiticide infestation, for example,have generally focused on use of insecticides, which are oftenunsuccessful or unsatisfactory for one or more of the following reasons:(1) failure of owner or applicator compliance (frequent administrationis required); (2) behavioral or physiological intolerance of the animalto the pesticide product or means of administration; (3) the emergenceof ectoparasites resistant to the reagent; and (4) negative impact onthe environment and/or toxicity.

Specifically, ticks parasitize wild as well as domesticated animals andhumans, and are known or suspected to be responsible for thetransmission of pathogens including bacteria, viruses and protozoanparasites. Currently, ticks are considered to be second in the world tomosquitoes as vectors of human diseases, but they are considered to bethe most important vector of pathogens in North America. Effectiveelimination of tick infestations is difficult and often impractical, dueto the need for concomitant treatment of the immediate host as well asthe environmental reservoir. Presently, tick control is effected byintegrated pest management in which different control methods areadapted to one area or against one tick species with due considerationto their environmental effects.

While the use of insecticides and pesticides have been beneficial,alternative or improved compounds, formulations, and methods are needed.Desirable compounds, formulations, and methods would not only providealternative therapies, but would also overcome one or more of thelimitations of current approaches. Such limitations include toxicity andsafety of both the animal and the user/owner, limited efficacy (e.g.,potency and duration), and resistance issues. Also impacting thebeneficial use of insecticides and pesticides are administrationobstacles, which include mode and recurrence of administration. Forexample, reducing the frequency of administration while maintainingefficacy is desirable, as excessive and repeated treatment of animals isoften inconvenient and/or difficult.

The present invention encompasses parasiticidal compounds, methods, andformulations for use in and on animals and plants, and which providealternative options for combating parasiticidal infestations,particularly ectoparasiticidal infestations. Further, certain aspects ofthe invention overcome at least some limitations in the use of currentinsecticides and pesticides, particularly in providing effective longterm, safe control of parasites.

Provided are compounds, and salts thereof, of formula I:

wherein A is

n is 0 or 1;

R¹ is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3of the same or different halo atoms;

R² is at each occurrence independently hydrogen, C₁-C₅ alkyl, C₃-C₆cycloalkyl, or C₁-C₅ haloalkyl;

R³ is

p is at each occurrence independently 0 or 1;

R⁴ is C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ cyanoalkyl, C₁-C₅ alkylthio,C₃-C₆ cycloalkyl optionally substituted with hydroxy, halo, or C₁-C₅alkyl: C₃-C₅ cycloheteroalkyl optionally substituted with C₁-C₅ alkyl,C₃-C₆ cycloalkyl, or C₁-C₅ haloalkyl: phenyl, thienyl, pyridinyl, or

wherein one of the carbons in said cycloalkyls, independently, orcycloheteroalkyl may form a carbonyl group, and wherein said phenyl,thienyl, or pyridinyl is optionally substituted with halo or a carbamoylgroup;

R⁵ is hydroxy, —O—(C₁-C₅ alkyl), or

R⁶ is hydrogen, C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ cyanoalkyl, C₁-C₅alkylthio, or C₂-C₅ alkynyl;

or R² and R³ combine to form, with the nitrogen to which they areattached,

Y₁, Y₂, and Y₃ are carbon or nitrogen with at most only one of Y₁, Y₂,and Y₃ being nitrogen, and when Y₁, Y₂, or Y₃ is a carbon, each may besubstituted by C₁-C₅ alkyl;

R⁷ is hydrogen, halo, C₁-C₅ alkyl, or

R⁸ is hydroxy, —O—(C₁-C₅ alkyl), or

R⁹ is C₁-C₅ alkyl,

and

R¹⁰ is hydrogen, C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ cyanoalkyl, C₁-C₅alkylthio, or C₂-C₅ alkynyl.

The invention provides a formulation, including a pharmaceuticalformulation, comprising a compound or salt of formula I and one or moreacceptable carriers. The formulation may further comprise at least oneadditional active ingredient. A pharmaceutical formulation of theinvention may be a human pharmaceutical formulation or a veterinarypharmaceutical formulation.

The invention provides a method of controlling ecto- and endoparasiteinfestations of an animal in need thereof comprising administering aneffective amount of a compound or salt of formula I to said animal. Themethod may further provide administering at least one other activeingredient to said animal. The animal may be a mammal, and may be ahuman or a companion animal, for example, a dog or cat.

The present invention provides a method for preventing and treatingdiseases transmitted through parasites comprising administering at leastone compound of the invention to an animal in need thereof.

The invention provides a method for controlling parasites, characterizedin that a compound of formula I is allowed to act on the pests and/ortheir habitat. The invention provides the use of compounds or saltsthereof of formula I for controlling pests.

The invention provides a compound or salt of formula I for use intherapy. The invention further provides a compound or salt of formula Ifor use in controlling ecto- and endoparasite infestations. Theinvention also provides use of a compound or salt of formula I for themanufacture of a formulation or medicament for controlling ecto- andendoparasite infestations.

The invention provides compounds of Formula II, or a salt thereof, ofthe formula

wherein n is 0 or 1;

R¹ is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3of the same or different halo atoms; and

R¹¹ is hydroxy, —O—(C₁-C₄ alkyl), or a halo atom.

These compounds have utility as intermediates in the processes forpreparing certain compounds of Formula I. These Formula II compounds maybe chemically modified to result in certain Formula I compounds.

The host animal may be a mammal or non-mammal, such as a bird (turkeys,chickens) or fish. Where the host animal is a mammal, it may be a humanor non-human mammal Non-human mammals include domestic animals, such aslivestock animals and companion animals. Livestock animals includecattle, camellids, pigs, sheep, goats, and horses. Companion animalsinclude dogs, rabbits, cats, and other pets owned and maintained inclose association with humans as part of the human-animal bond.

Parasites, sometimes also referred to as pests, include bothectoparasites and endoparasites. Ectoparasites include insect andacarine pests which commonly infest or infect animals, and include theegg, larval, pupal, nymphal, and adult stages thereof. Such pestsinclude fleas, lice, mosquitoes, mites, ticks, beetles, andblood-sucking, biting, or nuisance fly species. Endoparasites includenematode pests which commonly infect animals, and include the egg,larval, and adult stages thereof. Such pests include helminths(hookworms, tapeworms, heartworms), and are commercially importantbecause they cause serious diseases in animals, e.g. in sheep, pigs,goats, cattle, horses, donkeys, camels, dogs, cats, rabbits,guinea-pigs, hamsters, chicken, turkeys, guinea fowls and other farmedbirds, as well as exotic birds. Typical nematodes are Haemonchus,Trichostrcngyius, Qstertagia, Nematotiirus, Cooperia, Ascaris,Bunostonum, Gesophagostonum, Charbertia, Trichuris, Strongyius,Trïchonema, Dictyocaulus, Capsliarsa, Heterakis, Toxocara, Ascaridia,Oxyuris, Ancyiostoma, Uncinaria, Toxascaris and Parascaris. Thetrematodes include, in particular, the family of Fasciolideae,especially Fasciola hepatica.

Controlling refers to either ameliorating or eliminating a currentinfestation, or preventing an infestation, in or on an animal host or aplant.

Effective amount refers to the amount of a compound of formula I, or asalt thereof, sufficient to control an ecto- or endoparasiteinfestation, and includes causing a measurable reduction in the ecto- orendoparasite infestation population, and as such will depend uponseveral factors. For use on or in animals, ranges for a compound offormula I, or a salt thereof, in the methods include from 0.01 to 1000mg/kg and more desirably, 0.1 to 100 mg/kg of the animal's body weight.The frequency of the administration will also be dependent upon severalfactors, and can be a single dose administered once a day, once a week,or once a month, for a duration determined by the attending doctor orveterinarian. Additional active ingredients may be administered with acompound of formula I.

Pharmaceutically acceptable as used in this application, for examplewith reference to salts and formulation components such as carriers,includes “veterinarily acceptable”, and thus includes both human andanimal applications independently.

Salts of the compounds of the invention, including pharmaceuticallyacceptable salts, and common methodology for preparing them, are knownin the art. See, e.g., P. Stahl, et al., HANDBOOK OF PHARMACEUTICALSALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH, 2002); S. M.Berge, et al., “Pharmaceutical Salts,” Journal of PharmaceuticalSciences, Vol. 66, No. 1, January 1977.

The compounds of the invention and their salts may be formulated aspharmaceutical compositions for administration. Such pharmaceuticalcompositions and processes for making the same are known in the art forboth humans and non-human mammals. See, e.g., REMINGTON: THE SCIENCE ANDPRACTICE OF PHARMACY, (A. Gennaro, et al., eds., 19^(th) ed., MackPublishing Co., 1995). Formulations can be administered through variousmeans, including oral administration, parenteral administration such asinjection (intramuscular, subcutaneous, intravenous, intraperitoneal) orthe like; topical application with or without transdermal penetrationsuch as dipping, spray, bathing, washing, pouring-on and spotting-on,and dusting, or the like. Additional active ingredients may be includedin the formulation containing a compound of the invention or a saltthereof.

Carrier is used herein to describe any ingredient other than the activecomponent(s) in a formulation. The choice of carrier will to a largeextent depend on factors such as the particular mode of administrationor application, the effect of the carrier on solubility and stability,and the nature of the dosage form.

C₁-C₅ alkyl refers to straight chain and branched alkyls having one tofive carbon atoms, and includes methyl, ethyl, propyl, n-butyl,iso-butyl, pentyl, isopentyl, and neopentyl.

C₂-C₅ alkynyl refers to straight chain and branched alkynyls having twoto five carbon atoms, and includes ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 3-methyl-1-butynyl, pentynyl, isopentynyl, and neopentynyl.

Halogen or halo refers to fluorine, bromine, chlorine, and iodine.

Haloalkyl as used herein refers to an alkyl (as noted above) substitutedwith one or more halo atoms. Such groups include trifluoromethyl,difluoromethyl, fluoromethyl, methylchloride, dichloromethyl,pentylchloride, butyl chloride, and isopropyl chloride.

Cyanoalkyl as used herein refers to an alkyl (as noted above)substituted with a cyano group.

Alkylthio as used herein refers to an alkyl (as noted above) having asulfur in the group.

C₃-C₆ cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

C₃-C₅ cycloheteroalkyl refers to a saturated ring which has 3 to 5carbons and a hetero atom. The hetero atom may be sulfur, oxygen,nitrogen, or a sulfonyl group.

Diseases transmitted through parasites, particularly ectoparasites, are,for example bacterial, viral, rickettsial and protozoal vector-bornediseases. Examples of viral diseases transmitted through arboviruses,i.e. arthropod borne viruses, are Crimean-Congo Hemorhagic Fever (CCHF),Febrile illness, Papataci fever, Encephalitis, Meningitis, which arecaused by Bunyaviridae such as Bunyavirus, Nairovirus or Phlebovirus;Bluetongue, meningoencephalits, Febrile illness, hemorhagic fever, whichare caused by Reoviridae, such as Orbivirus, Colitivirus; Febrileillness, rash, encephalitis, polyarthritis, lymphadenitis, which arecaused by Togaviridae, such as Sindbisvirus, Chikungunya Virus;tick-borne meningoencephalitis, Dengue hemorhagic fever, encephalitis,Febrile illness, Yellow fever, which are caused by Flaviviridae, such asFlavivirus (including diverse sub-groups). Examples of bacterialdiseases transmitted through parasites are Rickettsiosis, such as RockyMountain spotted fever, tick typhus caused by infection throughRickettsia ssp; Tularemia caused by infection through Francisellatularensis; Borreliosis or Spirochaetosis, such as Lyme disease, orrelapsing fever, caused, by infection through Borrelia ssp.;Ehrllichiosis caused by infection through Ehrlichia ssp.; Plague, causedby infection through Yersinia ssp. Examples of protozoal or rickettsialborne diseases are Babesiosis, such as Texas fever, red water disease,Q-fever caused by infection through Babesia ssp.; Theileriosis, such ascast coast fever, Mediterranean coast fever, caused by infection throughTheileria ssp.; Nagana disease, Sleeping sickness caused by infectionthrough Trypanosoma ssp., Anaplasmosis caused by infection throughAnaplasma ssp.; Malaria caused by infection through Plasmodium ssp.;Leishmaniasis caused by infection through Leishmania ssp.

Given their activity, certain of the compounds of the invention aresuitable as soil insecticides against pests in the soil, as well asinsecticides for plants, such as cereals, cotton, rice, maize, soya,potatoes, vegetables, fruit, tobacco, hops, citrus, and avocados.Certain compounds according to the invention are suitable for protectingplants and plant organs, for increasing the harvest yields, and forimproving the quality of the harvested material which are encountered inagriculture, in horticulture, in forests, in gardens, and leisurefacilities, and in the protection of stored products and of materials.They may be employed as plant protection agents.

All plants and plant parts can be treated in accordance with theinvention. Plants are to be understood as meaning in the present contextall plants and plant populations such as desired and undesired wildplants or crop plants (including naturally occurring crop plants). Cropplants can be plants which can be obtained by conventional plantbreeding and optimization methods or by biotechnological and geneticengineering methods or by combinations of these methods, including thetransgenic plants and including the plant cultivars protectable or notprotectable by plant breeders' rights. Plant parts are to be understoodas meaning all parts and organs of plants above and below the ground,such as shoot, leaf, flower and root, examples which may be mentionedbeing leaves, needles, stalks, stems, flowers, fruit bodies, fruits,seeds, roots, tubers and rhizomes. The plant parts also includeharvested material, and vegetative and generative propagation material,for example cuttings, tubers, rhizomes, offshoots and seeds.

Treatment according to the invention of the plants and plant parts withthe active compounds is carried out by conventional and known means,including directly acting on, or by allowing the compounds to act on,the surroundings, habitat or storage space by the customary treatmentmethods, for example by immersion, spraying, evaporation, fogging,scattering, painting on, injection and, in the case of propagationmaterial, in particular in the case of seeds, also by applying one ormore coats.

The compounds can be converted to the customary formulations, such assolutions, emulsions, wettable powders, water- and oil-basedsuspensions, powders, dusts, pastes, soluble powders, soluble granules,granules for broadcasting, suspension-emulsion concentrates, naturalmaterials impregnated with active compound, synthetic materialsimpregnated with active compound, fertilizers and microencapsulations inpolymeric substances.

These formulations are produced in a known manner, for example by mixingthe active compounds with extenders, that is liquid solvents and/orsolid carriers, optionally with the use of surfactants, that isemulsifiers and/or dispersants and/or foam-formers. The formulations areprepared either in suitable plants or else before or during theapplication.

Suitable for use as auxiliaries are substances which are suitable forimparting to the composition itself and/or to preparations derivedtherefrom (for example spray liquors, seed dressings) particularproperties such as certain technical properties and/or also particularbiological properties. Typical suitable auxiliaries are extenders,solvents, and carriers.

Following are Schemes A-J and examples for preparing the compounds ofthe invention. The Schemes, examples, and information contained thereinare illustrative, and can be modified in ways known in the art to obtainthe desired results.

Preparation 1 Methyl2,2,2-trifluoro-1-(3,4,5-trichlorothiophen-2-yl)ethanone

Add a solution of n-BuLi (21.6 mL, 2.5 M in hexane, 54.0 mmol) to asolution of 2,3,4,5-tetrachloro-thiophene (10 g, 45.0 mmol) in dry THF(160 mL) at −78° C. and stir the mixture for 2 hours. Add a solution oftrifluoro-acetic acid ethyl ester (9.59 g, 67.6 mmol) in THF (15 mL) andstir at −78° C. for additional 2.5 hours. Quench the reaction withsaturated NH₄Cl solution (100 mL). Extract the aqueous mixture withEtOAc (100 mL×3). The combined organic layers are washed with brine,dried over anhydrous Na₂SO₄, and evaporate under vacuum. Purify theresidue by a flash column on silica gel eluting with PE:EtOAc (10:1 to5:1) to afford2,2,2-trifluoro-1-(3,4,5-trichloro-thiophen-2-yl)-ethanone as a brownoil (10.4 g, 81.9%). ¹³F NMR (400 MHz, CDCl₃) δ −73.38 (s, 3F).

Preparation 2 Methyl3-acetyl-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate

Add methyl 2-(2-oxopropylthio)acetate (35.4 g, 183.2 mmol) to a freshlyprepared solution of solid sodium (8.78 g, 381.5 mmol) in dry MeOH (300mL) at 0° C., followed by addition of a solution ofcyclohexane-1,2-dione (20 g, 152.6 mmol) in MeOH (30 mL). Stir themixture at 0° C. for 30 min and then at 50-60° C. for additional 1.5hour. Remove the solvent under vacuum and dilute the residue with water(100 mL). Extract the aqueous mixture with ethyl acetate (100 mL×3). Thecombined organic layers are washed with brine, dried over anhydrousNa₂SO₄, and evaporated under vacuum. Purify the residue by a flashcolumn on silica gel eluting with PE:EtOAc (50:1 to 30:1) to affordmethyl 3-acetyl-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate as awhite solid (10 g, 27.6%). MS (m/z): 239 (M+1).

Preparation 3 Methyl3-acetyl-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate

Stir a mixture of Cyclopentane-1,2-dione (2.00 g, 20.4 mmol), methyl2-(2-oxopropylthio)acetate (3.31 g, 20.4 mmol) and potassium carbonate(5.63 g, 40.8 mmol) in DMF (40 mL) at 80° C. for 4 hours. Filter off themixture and remove the solvent under vacuum. Purify the residue by aflash column on silica gel eluting with PE:EtOAc (8:1 to 6:1) to afford3-Acetyl-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methylester as a pale yellow solid (206 mg, 4.5%). MS (m/z): 225 (M+1).

Preparation 4 Methyl3-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate

Add a solution of LDA (2M in THF, 19.5 mL, 3.89 mmol) to a suspension of3-acetyl-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate (7.4 g, 3.11mmol) in dry THF (80 mL) at −78° C. under N₂. After stirring for 1.5 h,add 1-(3,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanone (9.9 g, 3.73 mmol)to the reaction mixture and stir the resultant mixture at the sametemperature for additional 2 hours. Quench the reaction with saturatedNH₄Cl aqueous solution. Extract the aqueous mixture with EtOAc (100mL×3).

The combined organic layers are washed with brine, dried over anhydrousNa₂SO₄ and concentrated under vacuum. Purify the residue by silica gelchromatograph (PE:EtOAc 50:1) to afford methyl3-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylateas an orange solid (9.1 g, 60.4%). MS (m/z): 481 (M+1).

The following compounds are prepared essentially by the method ofPreparation 4.

Prep. No. Chemical name Structure Physical data 5 3-[3-(3,5-Dichlorophenyl)-4,4,4- trifluoro-3-hydroxy- butyryl]-5,6-dihydro-4H-cyclopenta[c] thiophene-1- carboxylic acid methyl ester

MS (m/z): 465 (M − 1). 6 3-[4,4,4-Trifluoro-3- hydroxy-3-(3,4,5-trichloro-thiophen-2- yl)-butyryl]-4,5,6,7- tetrahydro-benzo[c]thiophene-1- carboxylic acid methyl ester

MS (m/z): 519 (M − 1). 7 3-[4,4,4-Trifluoro-3- hydroxy-3-(3,4,5-trichloro-phenyl)- butyryl]-4,5,6,7- tetrahydro-benzo[c]thiophene-1-carboxylic acid methyl ester

MS (m/z): 515 (M + 1) 8 3-[3-(3,5-Dichloro- 4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxy- butyryl]-4,5,6,7- tetrahydro-benzo[c]thiophene-1-carboxylic acid methyl ester

MS (m/z): 499 (M + 1) 9 3-[4,4,4-Trifluoro-3- hydroxy-3-(3,4,5-trichloro-phenyl)- butyryl]-5,6-dihydro- 4H-cyclopenta[c]thiophene-1-carboxylic acid methyl ester

MS (m/z): 501 (M + 1) 10 3-[3-(3,5-Dichloro- 4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxy- butyryl]-5,6-dihydro- 4H-cyclopenta[c]thiophene-1-carboxylic acid methyl ester

MS (m/z): 485 (M + 1)

Preparation 113-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylicacid methyl ester

Stir a mixture of methyl3-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxylbutanoyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate (9.1 g, 18.9mmol), SOCl₂ (9.0 g, 5.5 mL, 75.6 mmol) and pyridine (2.99 g, 3.1 mL,37.8 mmol) in anhydrous DCM (100 mL) at ambient temperature overnight.Dilute the resultant mixture with saturated NH₄Cl aqueous solution.Extract the aqueous mixture with DCM (100 mL×3). The combined organiclayers are washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. Purify the residue by silica gelchromatograph (PE:EtOAc 50:1) to afford3-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylicacid methyl ester as an orange solid (8.75 g, 100%). (m/z): 463 (M+1).

The following compounds are prepared essentially by the method ofPreparation 11.

Prep. No. Chemical name Structure Physical data 12 3-[3-(3,5-Dichloro-phenyl)-4,4,4- trifluoro-but-2- enoyl]-5,6-dihydro- 4H-cyclopenta[c]thiophene-1- carboxylic acid methyl ester

MS (m/z): 447 (M − 1). 13 3-[4,4,4-Trifluoro-3- (3,4,5-trichloro-thiophen-2-yl)-but- 2-enoyl]-4,5,6,7- tetrahydro-benzo[c] thiophene-1-carboxylic acid methyl ester] thiophene-1- carboxylic acid methyl ester

MS (m/z): 501 (M − 1). 14 3-[4,4,4-Trifluoro-3- (3,4,5-trichloro-phenyl)-but-2-enoyl]- 4,5,6,7-tetrahydro- benzo[c]thiophene-1-carboxylic acid methyl ester

MS (m/z): 497 (M + 1). 15 3-[3-(3,5-Dichloro- 4-fluoro-phenyl)-4,4,4-trifluoro-but-2- enoyl]-4,5,6,7- tetrahydro-benzo[c] thiophene-1-carboxylic acid methyl ester

MS (m/z): 481 (M + 1). 16 3-[4,4,4-Trifluoro-3- (3,4,5-trichloro-phenyl)-but-2-enoyl]- 5,6-dihydro-4H- cyclopenta[c] thiophene-1-carboxylic acid methyl ester

MS (m/z): 483 (M + 1). 17 3-[3-(3,5-Dichloro- 4-fluoro-phenyl)-4,4,4-trifluoro-but-2- enoyl]-5,6-dihydro- 4H-cyclopenta[c] thiophene-1-carboxylic acid methyl ester

MS (m/z): 467 (M + 1).

Preparation 183-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylicacid methyl ester

Stir a mixture of3-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylicacid methyl ester (8.75 g, 18.9 mmol), NaOH (2.65 g, 66.1 mmol) andNH₂OH—HCl (2.6 g, 37.8 mmol) in MeOH (60 mL) and water (15 mL) at roomtemperature for 2.5 hour. After removal of solvent under vacuum, dilutethe residue with ice water (50 mL). Acidify the aqueous mixture withconc. HCl to pH=1 and extract the resultant mixture with EtOAc (50mL×3). The combined organic layers are washed with brine, dried overanhydrous Na₂SO₄ and concentrated under vacuum. Purify the residue bysilica gel chromatograph (PE:EtOAc 50:1) to afford3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylicacid methyl ester as an orange solid (8.1 g, 93.1%). MS (m/z): 478(M+1).

The following compounds are prepared essentially by the method ofPreparation 18.

Prep. No. Chemical name Structure Physical data 19 3-[5-(3,5-Dichloro-phenyl)-5- trifluoromethyl-4,5- dihydro-isoxazol-3- yl]-5,6-dihydro-4H-cyclopenta[c] thiophene-1- carboxylic acid methyl ester

MS (m/z): 464 (M + 1). 20 3-[5-(3,4,5-Trichloro- thiophen-2-yl)-5-trifluoromethyl-4,5- dihydro-isoxazol-3- yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1- carboxylic acid methyl ester

MS (m/z): 516 (M − 1). 21 3-[5-(3,4,5-Trichloro- thiophen-2-yl)-5-trifluoromethyl-4,5- dihydro-isoxazol-3- yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1- carboxylic acid methyl ester

MS (m/z): 512 (M + 1). 22 3-[5-(3,5-Dichloro-4- fluoro-phenyl)-5-trifluoromethyl-4,5- dihydro-isoxazol-3- yl]-4,5,6,7-tetrahydro-benzo[c] thiophene-1- carboxylic acid methyl ester

MS (m/z): 496 (M + 1). 23 3-[5-(3,4,5-Trichloro- phenyl)-5-trifluoromethyl-4,5- dihydro-isoxazol-3- yl]-5,6-dihydro-4H-cyclopenta[c]thiophene- 1-carboxylic acid methyl ester

MS (m/z): 498 (M + 1). 24 3-[5-(3,5-Dichloro-4- fluoro-phenyl)-5-trifluoromethyl-4,5- dihydro-isoxazol-3-yl]- 5,6-dihydro-4H-cyclopenta[c]thiophene- 1-carboxylic acid methyl ester

MS (m/z): 482 (M + 1).

Preparation 253-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylicacid

Stir a mixture of3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylicacid methyl ester (8.1 g, 17.0 mmol) and LiOH—H₂O (3.57 g, 84.9 mmol) inMeOH (64 mL) and water (16 mL) at room temperature overnight. Afterremoval of organic solvent under vacuum, dilute the residue with icewater (80 mL). Acidify the aqueous mixture with conc. HCl to pH=1, andextract the resultant mixture with EtOAc (100 mL×3). The combinedorganic layers are washed brine, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. Purify the residue by silica gelchromatograph (PE:EtOAc 1:1) to afford3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylicacid as pale yellow solid (6.8 g, 86.4%). MS (m/z): 464 (M+1).

The following compounds may be prepared essentially by the method ofPreparation 25.

Prep. No. Chemical name Structure Physical data 62 3-[5-(3,5-Dichloro-phenyl)-5- trifluoromethyl-4,5- dihydro-isoxazol-3- yl]-5,6-dihydro-4H-cyclopenta[c] thiophene-1- carboxylic acid

MS (m/z): 448 (M − 1). 27 3-[5-(3,4,5-Trichloro- thiophen-2-yl)-5-trifluoromethyl-4,5- dihydro-isoxazol-3- yl]-4,5,6,7-tetrahydro-benzo[c]thiophene- 1-carboxylic acid

MS (m/z): 502 (M − 1). 28 3-[5-(3,4,5-Trichloro- phenyl)-5-trifluoromethyl-4,5- dihydro-isoxazol-3- yl]-4,5,6,7-tetrahydro-benzo[c]thiophene- 1-carboxylic acid

MS (m/z): 496 (M − 1). 29 3-[5-(3,5-Dichloro-4- fluoro-phenyl)-5-trifluoromethyl-4,5- dihydro-isoxazol-3- yl]-4,5,6,7-tetrahydro-benzo[c]thiphene-1- carboxylic acid

MS (m/z): 480 (M − 1). 30 3-[5-(3,5-Dichloro-4- fluoro-phenyl)-5-trifluoromethyl-4,5- dihydro-isoxazol-3- yl]-5,6-dihydro-4H-cyclopenta[c] thiophene-1- carboxylic acid

MS (m/z): 466 (M − 1). 31 3-[5-(3,4,5-Trichloro- phenyl)-5-trifluoromethyl-4,5- dihydro-isoxazol-3- yl]-5,6-dihydro-4H-cyclopenta[c] thiophene-1- carboxylic acid

MS (m/z): 482 (M − 1).

EXAMPLE 323-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide

Stir a mixture of3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylicacid (850 mg, 1.84 mmol), HATU (837 mg, 2.20 mmol) and DIEA (539 mg, 0.8mL, 4.6 mmol) in DCM (8 mL) at room temperature for 15 min, followed byaddition of (R)-3-aminopyrrolidin-2-one hydrochloride (315 mg, 2.76mmol). Stir the reaction mixture at room temperature for additional 1.5hour. Dilute the reaction mixture with water (20 mL) and extract withDCM (20 mL×3). The combined organic layers are washed brine, dried overanhydrous Na₂SO₄ and concentrated under vacuum. Purify the residue bypreparative HPLC to afford3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamideas a white solid (730 mg, 73.0%). MS (m/z): 546 (M+1); ¹H NMR (400 MHz,CDCl₃) δ 7.52-7.46 (m, 3H), 6.49 (s, 1H), 5.83 (s, 1H), 4.51-4.48 (m,1H), 4.22 (d, J=17.2, 1H), 3.85 (d, J=17.2, 1H), 3.52-3.47 (m, 2H),3.09-2.87 (m, 5H), 2.12-2.03 (m, 1H), 1.89-1.73 (m, 4H).

The following compounds may be prepared essentially by the method ofExample 32.

Ex. No. Chemical name Structure Physical data 33 N,N-Dimethyl-2-(4-{3-[5-(3,4,5-trichloro- thiophen-2-yl)-5- trifluoromethyl-4,5-dihydro-isoxazol-3-yl]- 4,5,6,7-tetrahydro- benzo[c]thiophene-1-carbonyl}-piperazin-1- yl)-acetamide

MS (m/z): 659 (M + 1); ¹H NMR (400 MHz, CDCl₃) δ 4.07-4.02 (m, 2H),3.68-3.80 (m, 4H), 3.49-3.41 (m, 2H), 3.09-3.01 (s, 3H), 3.01-2.95(S.3H), 2.91-2.85 (m, 2H), 2.84-2.78 (m, 4H), 2.69-2.63 (m, 2H),1.87-1.72 (m, 4H). Prep No. 34 ({3-[5-(3,5-Dichloro- phenyl)-5-trifluoromethyl-4,5- dihydro-isoxazol-3-yl]- 4,5,6,7-tetrahydro-benzo[c]thiophene-1- carbonyl}-amino)- acetic acid methyl ester

MS (m/z): 535 (M + 1). Prep No. 35 ({3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5- trifluoromethyl-4,5- dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro- benzo[c]thiophene-1- carbonyl}-amino)- acetic acidmethyl ester

MS (m/z): 575 (M + 1). 36 3-(5-(3,5- dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- N-(2-oxo-2-(2,2,2-trifluoroethylamino) ethyl)-5,6-dihydro-4H- cyclopenta[c]thiophene-1-carboxamide

MS (m/z): 588 (M + 1); ¹H NMR (400 MHz, CDCl₃) 67.52-7.48 (m, 2H),7.48-7.44 (m, 1H), 7.01-6.95 (s, 1H), 6.79-6.71 (s, 1H), 4.21-4.18 (m,2H), 4.06-3.91 (m, 3H), 3.65-3.59 (d, J = 17.2, 1H), 2.98-2.87 (m, 4H),2.59-2.49 (m, 2H). 37 3-[5-(3,5-Dichloro- phenyl)-5-trifluoromethyl-4,5- dihydro-isoxazol-3-yl]- 4,5,6,7-tetrahydro-benzo[c]thiophene-1- carboxylic acid (1,1- dioxo-thietan-3- yl)-amide

MS (m/z): 567 (M + 1); ¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 2H), 7.44 (s,1H), 6.59-6.58 (s, 1H), 4.91-4.89 (m, 1H), 4.64-4.59 (m, 2H), 4.07-4.03(m, 3H), 3.70-3.65 (m, 1H), 2.97-2.91 (m, 4H), 1.80-1.86 (m, 4H). 383-(5-(3,5- dichlorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(3-oxocyclohexyl)- 4,5,6,7-tetrahydrobenzo[c]thiophene-1- carboxamide

MS (m/z): 559 (M + 1); ¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 2H), 7.43 (s,1H), 5.73 (d, J = 7.6 Hz, 1H), 4.46-4.42 (m, 1H), 4.06-4.02 (d, J = 16Hz, 1H), 3.68-3.64 (d, J = 16 Hz, 1H), 2.93-2.89 (m, 4H), 2.82-2.77 (m,1H), 2.47-2.30 (m, 3H), 2.17-2.15 (m, 1H), 2.02-1.95 (m, 1H), 1.88-1.78(m, 6H). 39 3-[5-(3,5-Dichloro- phenyl)-5- trifluoromethyl-4,5-dihydro-isoxazol-3-yl]- 4,5,6,7-tetrahydro- benzo[c]thiophene-1-carboxylic acid (1,1-dioxo-hexahydro- 116-thiopyran-4-yl)- amide

MS (m/z): 559 (M + 1); ¹H NMR (400 MHz, CDCl₃) δ 7.49-7.44 (m, 3H), 5.77(d, J = 7.6 Hz, 1H), 4.27-4.10 (m, 1H), 4.04 (d, J = 17.2 Hz, 1H), 3.66(d, J = 17.2 Hz, 1H), 3.20-3.05 (m, 4H), 2.94-2.86 (m, 4H), 2.42-2.40(m, 2H), 2.26-2.16 (m, 2H), 1.79-1.74 (m, 4H). 40 3-[5-(3,5-Dichloro-phenyl)-5- trifluoromethyl-4,5- dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro- benzo[c]thiphene-1- carboxylic acid [2-oxo-1-(2,2,2-trifluoro-ethyl)- pyrrolidin-3-yl]-amide

MS (m/z): 628 (M + 1); ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.43 (m, 3H),6.65-6.56 (m, 1H), 4.61-4.51 (m, 1H), 4.18-4.01 (m, 2H), 3.99-3.51 (m,4H), 3.09-2.81 (m, 5H), 2.11-1.99 (m, 1H), 1.81-1.72 (m, 4H). 413-(5-(3,5- dichlorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-((R)-2-oxopyrrolidin- 3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene- 1-carboxamide

MS (m/z): 532 (M + 1); ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.48 (m, 2H),7.48-7.44 (m, 1H), 6.59-6.50 (s, 1H), 6.14-6.08 (s, 1H), 4.48-4.41 (m,1H), 4.06-3.94 (d, J = 17.2, 1H), 3.65-3.59 (d, J = 17.2, 1H), 3.51-3.42(m, 2H), 3.07-2.84 (m, 5H), 2.58-2.48 (m, 2H), 2.11-2.01 (m, 1H). 42N-(2- (cyanomethylamino)-2- oxoethyl)-3-(5-(3,5- dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- 5,6-dihydro-4H-cyclopenta[c]thiophene- 1-carboxamide

MS (m/z): 545 (M + 1); ¹H NMR (400 MHz, CDCl₃) δ 7.58-7.52 (s, 1H),7.52-7.48 (m, 2H), 7.48-7.44 (m, 1H), 6.86-6.78 (s, 1H), 4.26-4.19 (m,4H), 4.04-3.97 (d, J = 17.2, 1H), 3.65-3.59 (d, J = 17.2, 1H), 3.09-2.84(m, 4H), 2.58-2.48 (m, 2H). 43 3-(5-(3,5- dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6- dihydro-4H-cyclopenta [c]thiophene-1- carboxamide

MS (m/z): 544 (M + 1); ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.48 (m, 2H),7.48-7.44 (m, 1H), 6.86-6.68 (m, 2H), 4.19-4.05 (m, 4H), 4.04-3.97 (d, J= 17.2, 1H), 3.65-3.59 (d, J = 17.2, 1H), 3.03-2.87 (m, 4H), 2.58-2.48(m, 2H), 2.29-2.26 (s, 1H). 44 N-(2-oxo-2-(2,2,2- trifluoroethylamino)ethyl)-3-(5-(3,4,5- trichlorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- 4,5,6,7-tetrahydrobenzo [c]thiophene-1-carboxamide

MS (m/z): 636 (M + 1); ¹H NMR (400 MHz, CDCl₃) δ 7.62 (s, 2H), 7.32 (br,1H), 6.95 (br, 1H), 4.26-4.25 (m, 2H), 4.06-3.83 (m, 3H), 3.66 (d, J =16.8 Hz, 1H), 2.98-2.89 (m, 4H), 1.79 (br, 4H). 45N-((R)-2-oxopyrrolidin- 3-yl)-3-(5-(3,4,5- trichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- 4,5,6,7-tetrahydrobenzo[c]thiophene-1- carboxamide

MS (m/z): 580 (M + 1); ¹H NMR (400 MHz, CDCl₃) δ 7.62 (s, 2H), 6.62 (br,1H), 6.17 (br, 1H), 4.47-4.46 (m, 1H), 4.07-4.02 (m, 1H), 3.75-3.64 (m,1H), 3.49-3.43 (m, 2H), 3.02-2.88 (m, 2H), 2.09-2.01 (m, 1H), 1.77 (br,4H). 46 N-(2- (cyanomethylamino)-2- oxoethyl)-3-(5-(3,4,5-trichlorophenyl)-5- (trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophene-1- carboxamide

MS (m/z): 593 (M + 1); ¹H NMR (CDCl₃, 400 MHz) δ 7.63 (s, 2 H), 7.47 (m,1 H), 6.81 (m, 1 H), 4.22 (m, 4 H), 4.06 (d, J = 17.2, 1 H), 3.70 (d, J= 17.2, 1 H), 2.90 (m, 4 H), 1.79 (m, 4 H). 47 N-(2-oxo-2-(prop-2-ynylamino)ethyl)-3-(5- (3,4,5-trichlorophenyl)- 5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- 4,5,6,7-tetrahydrobenzo [c]thiophene-1-carboxamide

MS (m/z): 592 (M + 1); ¹H NMR (CDCl₃, 400 MHz) δ 7.63 (s, 2 H), 6.78 (m,1 H), 6.50 (m, 1 H), 4.15 (m, 2 H), 4.10 (m, 2 H), 4.05 (d, J = 16.8, 1H), 3.67 (d, J = 16.8, 1 H), 2.95 (m, 2 H), 2.90 (m, 2 H), 2.26 (m, 1H), 1.79 (m, 4H). 48 3-(5-(3,5-dichloro-4- fluorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- N-(2-oxo-2-(2,2,2-trifluoroethylamino) ethyl)-4,5,6,7- tetrahydrobenzo[c]thiophene-1-carboxamide

MS (m/z): 620 (M + 1); ¹H NMR (CDOD₃, 400 MHz) δ 7.76 (d, J = 6.4, 2H),4.25 (d, J = 17.6, 1H), 4.07 (s, 2H), 4.04-3.92 (m, 3H), 3.01-2.98 (m,2H), 2.90-2.89 (m, 2H), 1.79 (m, 4H). 49 3-(5-(3,5-dichloro-4-fluorophenyl)-5- (trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-N-((R)-2-oxopyrrolidin-3- yl)-4,5,6,7- tetrahydrobenzo[c]thiophene-1-carboxamide

MS (m/z): 564 (M + 1); ¹H NMR (CDOD₃, 400 MHz) δ 7.76 (d, J = 6.4, 2H),4.63 (t, J = 9.6, 1H), 4.24 (d, J = 17.6, 1H), 4.02 (d, J = 17.6, 1H),3.44-3.40 (m, 2H), 2.99-2.98 (m, 2H), 2.89 (m, 2H), 2.59-2.52 (m, 1H),2.23-2.18 (m, 1H), 1.79-1.77 (m, 4H). 50 N-(2- (cyanomethylamino)-2-oxoethyl)-3-(5-(3,5- dichloro-4-fluorophenyl)- 5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- 4,5,6,7-tetrahydrobenzo [c]thiophene-1-carboxamide

MS (m/z): 577 (M + 1); ¹H NMR (CDOD₃, 400 MHz) δ 7.77 (d, J = 6.4, 2H),4.28-4.21 (m, 3H), 4.05-4.00 (m, 3H), 3.00 (t, J = 6.0, 2H), 2.93-2.90(m, 2H), 1.81-1.80 (m, 4H). 51 3-(5-(3,5-dichloro-4- fluorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- N-(2-oxo-2-(prop-2-ynylamino)ethyl)- 4,5,6,7-tetrahydrobenzo [c]thiophene-1- carboxamide

MS (m/z): 576 (M + 1); ¹H NMR (CDOD₃, 400 MHz) δ 7.76 (d, J = 6.4, 2H),4.24 (d, J = 17.6, 1H), 4.03-3.99 (m, 5H), 2.98 (t, J = 6.0, 2H),2.88-2.86 (m, 2H), 2.62 (t, J = 2.4, 1H), 1.79-1.77 (m, 4H). 52N-(2-oxo-2-(2,2,2- trifluoroethylamino) ethyl)-3-(5-(3,4,5-trichlorophenyl)-5- (trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-5,6-dihydro-4H- cyclopenta[c]thiophene- 1-carboxamide

MS (m/z): 622 (M + 1); ¹H NMR (CDCl3, 400 MHz) δ 7.64 (s, 2 H), 6.81(brs, 1 H), 6.73 (brs, 1 H), 4.22 (d, J = 4.8, 2 H), 3.99 (m, 3 H), 3.64(d, J = 17.2, 1 H), 2.99 (t, J = 7.6, 2 H), 2.91 (t, J = 7.6, 2 H), 2.55(m, 2 H). 53 N-((R)-2-oxopyrrolidin- 3-yl)-3-(5-(3,4,5-trichlorophenyl)-5- (trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-5,6-dihydro-4H- cyclopenta[c]thiophene- 1-carboxamide

MS (m/z): 566 (M + 1); ¹H NMR (CDCl3, 400 MHz) δ 7.62 (s, 2 H), 6.46(brs, 1 H), 6.16 (brs, 1 H), 4.47 (m, 1 H), 3.99 (d, J = 17.2, 1 H),3.61 (d, J = 17.2, 1 H), 3.47 (m, 2 H), 2.93 (m, 5 H), 2.53 (m, 2 H),2.09 (m, 1 H). 54 N-(2- (cyanomethylamino)-2- oxoethyl)-3-(5-(3,4,5-trichlorophenyl)-5- (trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-5,6-dihydro-4H- cyclopenta[c]thiophene- 1-carboxamide

MS (m/z): 579 (M + 1); ¹H NMR (CDCl3, 400 MHz) δ 7.62 (s, 2H), 7.21(brs, 1 H), 6.71 (brs, 1 H), 4.22 (d, J = 6.0, 2 H), 4.18 (d, J = 5.2, 2H), 4.02 (d, J = 17.2, 1 H), 3.63 (d, J = 17.2, 1 H), 2.96 (t, J = 7.2,2 H), 2. 89 (t, J = 7.2, 2 H), 2.56 (m, 2 H). 55 N-(2-oxo-2-(prop-2-ynylamino)ethyl)-3-(5- (3,4,5-trichlorophenyl)- 5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- 5,6-dihydro-4H- cyclopenta[c]thiophene-1-carboxamide

MS (m/z): 578 (M + 1); ¹H NMR (CDCl3, 400 MHz) δ 7.62 (s, 2 H), 6.82(brs, 1 H), 6.65 (brs, 1 H), 4.15 (d, J = 4.8, 2 H), 4.10 (d, J₁ = 2.4,J₂ = 4.2, 2 H), 4.02 (d, J = 16.8, 1 H), 3.62 (d, J = 16.8, 1 H), 2.98(t, J = 7.2, 2 H), 2. 88 (t, J = 7.2, 2 H), 2.55 (m, 2 H), 2. 27 (t, J =2.4, 2 H). 56 N-(2-oxo-1-(2,2,2- trifluoroethyl) pyrrolidin-3-yl)-3-(5-(3,4,5- trichlorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- 5,6-dihydro-4H- cyclopenta[c]thiophene-1-carboxamide

MS (m/z): 648 (M + 1); ¹H NMR (CDCl3, 400 MHz) δ 7.62 (s, 2 H), 6.5(brs, 1 H), 4.50 (m, 1 H), 4.09 (m, 1 H), 4.00 (d, J = 17.2, 1 H), 3.84(m, 1 H), 3.58 (m, 3 H), 2. 93 (m, 5 H), 2.52 (m, 2 H), 2.04 (m, 1 H).57 3-(5-(3,5-dichloro-4- fluorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(2-oxo-2-(2,2,2- trifluoroethylamino)ethyl)-5,6-dihydro-4H- cyclopenta[c]thiophene- 1-carboxamide

MS (m/z): 606 (M + 1); ¹H NMR (CDCl3, 400 MHz) δ 7.56 (d, J = 6.0, 2 H),6.92 (t, J = 6.4, 1 H), 6.76 (t, J = 4.8, 1 H), 4.21 (d, J = 4.8, 1 H),3.98 (m, 3 H), 3.61 (d, J = 16.8, 1 H), 2.97 (t, J = 7.6, 2 H), 2.89 (t,J = 7.6, 2 H), 2.55 (m, 2H) 58 3-(5-(3,5-dichloro-4- fluorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- N-((R)-2-oxopyrrolidin-3-yl)-5,6-dihydro-4H- cyclopenta[c]thiophene- 1-carboxamide

MS (m/z): 550 (M + 1); ¹H NMR (CDCl3, 400 MHz) δ 7.56 (d, J = 6.4, 2 H),6.46 (brs, 1 H), 6.32 (brs, 1 H), 4.47 (m, 1 H), 3.99 (d, J = 17.2, 1H), 3.61 (d, J = 17.2, 1 H), 3.48 (m, 2 H), 2. 93 (m, 5 H), 2.53 (m, 2H), 2.06 (m, 1 H). 59 N-(2- (cyanomethylamino)- 2-oxoethyl)-3-(5-(3,5-dichloro-4- fluorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- 5,6-dihydro-4H- cyclopenta[c]thiophene-1-carboxamide

MS (m/z): 563 (M + 1); ¹H NMR (CDCl3, 400 MHz) δ 7.56 (d, J = 6.0, 2 H),7.41 (brs, 1 H), 6.84 (brs, 1 H), 4.20 (m, 4H), 3.99 (d, J = 16.8, 1 H),3.63 (d, J = 16.8, 1 H), 2.95 (t, J = 7.2, 2 H), 2. 88 (t, J = 7.2, 2H), 2.53 (m, 2 H). 60 3-(5-(3,5-dichloro-4- fluorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- N-(2-oxo-1-(2,2,2-trifluoroethyl) pyrrolidin-3-yl)-5,6- dihydro-4H-cyclopenta[c]thiophene-1- carboxamide

MS (m/z): 632 (M + 1); ¹H NMR (CDCl3, 400 MHz) δ 7.58 (d, J = 6.0, 2H),6.60-6.57 (m, 1H), 4.56-4.50 (m, 1H), 4.14-4.00 (m, 2H), 3.87-3.83 (m,1H), 3.67-3.55 (m, 3H), 3.01-2.86 (m, 5H), 2.57-2.50 (m, 2H), 2.10-2.05(m, 1H). 61 3-(5-(3,5-dichloro-4- fluorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6- dihydro-4H-cyclopenta [c]thiophene-1- carboxamide

MS (m/z): 562 (M + 1); ¹H NMR (CDCl3, 400 MHz) δ 7.58 (d, J = 6.0, 2H),6.85 (brs, 1H), 6.70 (brs, 1H), 4.18 (d, J = 4.8, 2H), 4.14-4.12 (m,2H), 4.04 (d, J = 17.2, 1H), 3.65 (d, J = 17.2, 1H), 3.00 (t, J = 7.2,2H), 2.90 (t, J = 7.2, 2H), 2.60-2.55 (m, 2H), 2.29 (s, 1H). 623-(5-(3,5- dichlorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(2-oxo-2-(2,2,2- trifluoroethylamino)ethyl)-4,5,6,7- tetrahydrobenzo[c] thiophene-1- carboxamide

MS (m/z): 602 (M + 1); ¹H NMR (CDCl3, 400 MHz) δ 7.52-7.46 (m, 3H),7.12-7.01 (m, 1H), 6.85-6.78 (m, 1H), 4.28-4.20 (m, 2H), 4.08-3.91 (m,3H), 3.68 (d, J = 17.2, 1H), 3.07-2.87 (m, 4H), 1.89-1.73 (m, 4H). 633-(5-(3,5- dichlorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(2-(ethylamino)-2- oxoethyl)-4,5,6,7-tetrahydrobenzo[c] thiophene-1- carboxamide

MS (m/z): 548 (M + 1); ¹H NMR (CDCl3, 400 MHz) δ¹H NMR (CDCl3, 400 MHz)δ 7.49 (s, 2H), 7.42 (m, 1H), 6.80 (s, 1H), 5.96 (s, 1H), 4.09-4.02 (m,3H), 3.69-3.65 (d, J = 16 Hz, 1H), 3.40-3.33 (m, 2H), 3.00 (s, 2H),2.92-2.90 (m, 2H), 1.79 (s, 4H), 1.26-1.17 (m, 3H). 64 3-(5-(3,5-dichlorophenyl)-5- (trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-N-((tetrahydrofuran- 2-yl)methyl)-4,5,6,7- tetrahydrobenzo[c]thiophene-1- carboxamide

MS (m/z): 547 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.48 (s, 2H), 7.42 (s,1H), 6.23 (s, 1H), 4.08-4.02 (m, 2H), 3.91-3.86 (m, 1H), 3.81-3.76 (m,2H), 3.69-3.65 (m, J = 16 Hz, 1H), 3.34-3.28 (m, 1H), 3.00-2.85 (m, 4H),2.06-1.98 (m, 1H), 1.96-1.89 (m, 2H), 1.79-1.77 (m, 4H), 1.64-1.59 (m,1H). 65 3-(5-(3,5- dichlorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(2-(methylthio) ethyl)-4,5,6,7-tetrahydrobenzo[c] thiophene-1- carboxamide

MS (m/z): 537 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.49 (s, 2H), 7.43 (s,1H), 6.33 (s, 1H), 4.07-4.03 (d, J = 16 Hz, 1H), 3.69-3.62 (m, 3H), 2.98(s, 2H), 2.92-2.90 (m, 2H), 2.76-2.74 (m, 2H), 2.14 (s, 3H), 1.80-1.79(m, 4H). 66 3-(5-(3,5- dichlorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(3,3,3- trifluoropropyl)-4,5,6,7-tetrahydrobenzo [c]thiophene-1- carboxamide

MS (m/z): 559 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.49 (s, 2H), 7.43 (s,1H), 6.08-6.05 (m, 1H), 4.06-4.02 (d, J = 16 Hz, 1H), 3.72-3.64 (m, 3H),2.94-2.85 (m, 4H), 2.51-2.40 (m, 2H), 1.80-1.78 (m, 4H). 67 3-(5-(3,5-dichlorophenyl)-5- (trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- N-(3-hydroxycyclohexyl)- 4,5,6,7-tetrahydrobenzo [c]thiophene-1- carboxamide

MS (m/z): 561 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.49 (s, 2H), 7.43 (s,1H), 6.85 (s, 1H),4.21 (s, 1H), 4.09-4.02 (m, 2H), 3.69-3.64 (d, J=20Hz, 1H), 2.96-2.89 (m, 5H), 2.05-1.78 (m, 9H), 1.49-1.38 (m, 2H). 683-(5-(3,5- dichlorophenyl)- 5-(trifluoromethyl)- 4,5-dihydroisoxazol-3-yl)-N-(5-fluoropyridin- 2-yl)-4,5,6,7- tetrahydrobenzo[c] thiophene-1-carboxamide

MS (m/z): 558 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 8.32-8.29(m, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.51-7.44 (m, 3H), 7.43 (s, 1H),4.09-4.05 (d, J = 16 Hz, 1H), 3.71-3.67 (d, J = 16 Hz, 1H), 3.09 (s,2H), 2.94-2.93 (m, 2H), 1.83 (s, 4H) 69 3-(5-(3,5- dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- N-(tetrahydro-2H-pyran-3-yl)-4,5,6,7- tetrahydrobenzo[c] thiophene-1- carboxamide

MS (m/z): 547 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.49 (s, 2H), 7.40 (s,1H), 6.23 (d, J = 9.6 Hz, 1H), 4.18-4.16 (s, 1H), 4.07-4.03 (d, J = 16Hz, 1H), 3.83-3.77 (m, 2H), 3.69-3.57 (m, 3H), 2.98-2.90 (m, 4H),1.90-1.75 (m, 8H). 70 3-(5-(3,5- dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- N-(thietan-3-yl)- 4,5,6,7-tetrahydrobenzo[c] thiophene-1- carboxamide

MS (m/z): 535 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.49 (s, 2H), 7.44 (s,1H), 6.18 (d, J = 7.6 Hz, 1H), 5.40-5.34 (m, 1H), 4.06 (d, J = 17.2 Hz,1H), 3.66 (d, J = 17.2 Hz, 1H), 3.46-3.36 (m, 4H), 2.97-2.90 (m, 4H),1.81-1.78 (m, 4H). 71 3-(5-(3,5- dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- N-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydrobenzo[c] thiophene-1- carboxamide

MS (m/z): 547 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.47 (s, 2H), 7.41 (s,1H), 5.74-5.72 (d, J = 7.6 Hz, 1H), 4.19-4.11 (m, 1H), 4.10-4.06 (d, J =16 Hz, 1H), 4.04-3.96 (m, 2H), 3.69-3.65 (d, J = 16 Hz, 1H), 3.53-3.43(m, 2H), 2.94-2.88 (m, 4H), 2.00-1.97 (m, 2H), 1.77 (s, 4H), 1.60-1.50(m, 2H). 72 N-(1-cyclopropyl-2- oxopyrrolidin-3-yl)-3-(5-(3,5-dichlorophenyl)- 5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophene-1- carboxamide

MS (m/z): 586 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.49 (s, 2 H), 7.43 (s,1H), 6.50 (brs, 1 H), 4.43-4.40 (m, 1 H), 4.04 (d, J = 16.8, 1 H), 3.65(d, J = 16.8, 1 H), 3.42-3.30 (m, 2 H), 2.99-2.82 (m, 5 H), 1.91-1.80(m, 5 H), 0.83-0.763 (m, 4 H) 73 N-(2-oxo-2-(prop-2-ynylamino)ethyl)-3-(5- (3,4,5- trichlorothiophen-2-yl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- 4,5,6,7-tetrahydrobenzo[c]thiophene-1- carboxamide

MS (m/z): 600 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 6.92-6.77 (m, 2H),4.21-4.09 (m, 4H), 4.08-4.04 (m, 2H), 3.09-2.88 (m, 4H), 1.87-1.71 (m,4H). 75 3-[5-(3,4,5-Trichloro- phenyl)-5- trifluoromethyl-4,5-dihydro-isoxazol-3- yl]-4,5,6,7-tetrahydro- benzo[c]thiophene-1-carboxylic acid (1,1-dioxo-hexahydro- thiopyran-4-yl)-amide

MS (m/z): 631 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.62 (s, 2H), 5.89-5.87(m, 1H), 4.28-4.20 (m, 1H), 4.07-4.03 (d, J = 16 Hz, 1H), 3.70-3.66 (d,J = 16 Hz, 1H), 3.20-3.12 (m, 4H), 2.94-2.89 (m, 4H), 2.42-2.39 (m, 2H),2.27-2.17 (m, 2H), 1.79 (s, 4H). 76 N-(2-oxo-1-(2,2,2- trifluoroethyl)pyrrolidin-3-yl)-3-(5- (3,4,5- trichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- 4,5,6,7-tetrahydrobenzo[c]thiophene-1- carboxamide

MS (m/z): 664 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.63 (s, 2 H), 6.45(brs, 1 H), 4.53 (brs, 1 H), 4.09 (m, 2 H), 3.85 (m, 1 H), 3.58 (m, 3H), 2.95 (m, 4 H), 2.02 (m, 1 H), 1.79 (m, 4 H). 77 N-(tetrahydro-2H-pyran-4-yl)-3-(5-(3,4,5- trichlorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- 4,5,6,7-tetrahydrobenzo [c]thiophene-1-carboxamide

MS (m/z): 583 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.61 (s, 2H), 5.70-5.68(d, J = 8.0 Hz, 1H), 4.19-4.11 (m, 1H), 3.70-3.66 (d, J = 16 Hz, 1H),4.00-3.97 (m, 2H), 3.68-3.64 (d, J = 16 Hz, 1H), 3.54-3.48 (m, 2H),2.94-2.88 (m, 4H), 2.00-1.98 (m, 2H), 1.79 (s, 4H), 1.64-1.50 (m, 2H).78 N-(1-cyclopropyl-2- oxopyrrolidin-3-yl)-3- (5-(3,4,5-trichlorophenyl)-5- (trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophene-1- carboxamide

MS (m/z): 622 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 8.00 (s, 2 H), 6.53(brs, 1 H), 4.43 (m, 1 H), 4.04 (d, J = 17.2, 1 H), 3.65 (d, J = 17.2, 1H), 3.36 (m, 2 H), 2.83 (m, 5 H), 2.73 (m, 1 H), 1.84 (m, 5H), 0.79 (m,4 H). 79 3-[5-(3,5-Dichloro-4- fluoro-phenyl)-5- trifluoromethyl-4,5-dihydro-isoxazol-3-yl]- 4,5,6,7-tetrahydro-benzo [c]thiophene-1-carboxylic acid (1,1-dioxo-thietan- 3-yl)-amide

MS (m/z): 585 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.76 (d, J = 6.0, 2H),4.65-4.56 (m, 1H), 4.53 (t, J = 4.8, 2H), 4.28-4.23 (m, 3H), 4.02 (d, J= 17.6, 1H), 2.97 (t, J = 6.0, 2H), 2.90 (t, J = 6.0, 2H), 1.80-1.76 (m,4H). 80 3-[5-(3,5-Dichloro-4- fluoro-phenyl)-5- trifluoromethyl-4,5-dihydro-isoxazol-3-yl]- 4,5,6,7-tetrahydro-benzo [c]thiophene-1-carboxylicacid (1,1- dioxo-hexahydro- thiopyran-4-yl)-amide

MS (m/z): 613 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.56 (d, J = 6.0, 2 H),5.75 (d, J = 7.2, 1 H), 4.06 (d, J = 16.8, 1 H), 3.65 (d, J = 16.8, 1H), 3.13 (m, 4H), 2.91 (m, 4 H), 2.41 (m, 2 H), 2.23 (m, 2 H), 1.84 (m,4H). 81 3-(5-(3,5-dichloro-4- fluorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(4-oxocyclohexyl)- 4,5,6,7-tetrahydrobenzo[c]thiophene-1- carboxamide

MS (m/z): 577 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.48 (d, J = 6.0, 2H),5.67 (d, J = 6.8, 1H), 4.33 (m, 1H), 3.98 (d, J = 16.8, 1H), 3.58 (d, J= 16.8, 1H), 2.82 (m, 4H), 2.40 (m, 6H), 1.65 (m, 6H) 823-(5-(3,5-dichloro-4- fluorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(2-oxo-1-(2,2,2- trifluoroethyl)pyrrolidin-3-yl)- 4,5,6,7-tetrahydrobenzo [c]thiophene-1- carboxamide

MS (m/z): 646 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7. 50 (dd, J₁ = 2.4, J₂= 6.0, 2 H), 6.44 (dd, J₁ = 4.8, J₂ = 12.0, 1 H), 4.46 (m, 1 H), 3.98(m, 2H), 3.78 (m, 1 H), 3.55 (m, 3 H), 2.83 (m, 5 H), 1.963 (m, 1 H),1.71 (m, 4 H). 83 3-(5-(3,5-dichloro-4- fluorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- N-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydrobenzo[c] thiophene-1- carboxamide

MS (m/z): 565 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.49 (d, J = 5.6, 2 H),5.59 (d, J = 7.6, 1 H), 4.10 (m, 1 H), 3.98 (d, J = 16.8, 1 H), 3.91 (m,2 H), 3.58 (d, J = 16.8, 1 H), 3.45 (m, 2 H), 2.84 (m, 4 H), 1.95 (m, 2H), 1.72 (m, 4 H), 1.49 (m, 3 H). 84 N-(1-cyclopropyl-2-oxopyrrolidin-3-yl)-3- (5-(3,5-dichloro-4- fluorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- 4,5,6,7-tetrahydrobenzo[c]thiophene-1- carboxamide

MS (m/z): 604 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.77 (d, J = 6.0, 2H),4.62 (t, J = 9.6, 1H), 4.24 (d, J = 17.6, 1H), 4.02 (d, J = 17.6, 1H),3.43-3.39 (m, 2H), 2.99-2.96 (m, 2H), 2.90-2.88 (m, 2H), 2.75-2.69 (m,1H), 2.50-2.42 (m, 1H), 2.10-1.99 (m, 1H), 1.81-1.78 (m, 4H), 0.85-0.82(m, 4H). 85 3-(5-(3,5- dichlorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(4-oxocyclohexyl)- 5,6-dihydro-4H-cyclopenta[c] thiophene-1- carboxamide

MS (m/z): 545 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.52-7.44 (m, 3H),5.72-5.68 (m, 1H), 4.48-4.37 (m, 1H), 4.04-3.97 (d, J = 17.2, 1H),3.65-3.59 (d, J = 17.2, 1H), 2.92-2.84 (m, 4H), 2.58-2.48 (m, 6H),2.47-2.31 (m, 2H), 1.84-1.71 (m, 2H). 86 3-(5-(3,5- dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)- N-(2-oxo-1-(2,2,2-trifluoroethyl) pyrrolidin-3-yl)-5,6- dihydro-4H-cyclopenta[c]thiophene-1- carboxamide

MS (m/z): 614 (M + 1); 1H NMR (CDCl3, 400 MHz) δ 7.52-7.44 (m, 3H),6.43-6.38 (s, 1H), 4.52-4.48 (m, 1H), 4.17-4.05 (m, 2H), 4.04-3.97 (d, J= 17.2, 1H), 3.89-3.77 (m, 1H), 3.68-3.51 (m, 3H), 2.93-2.82 (m, 5H),2.58-2.46 (m, 2H), 2.08-1.97 (m, 1H).

EXAMPLE 87 A3-((R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamideand B3-((S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide

Separate3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide(6.2 g 11.29 mmol) by SFC (Column: Chiralcel OD 250830 mm I.D., Sum.Mobile phase: Supercritical CO₂/MeOH=60/40, Flow rate: 200 ml/min) toafford two diastereoisomers3-((R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide (2.7g, 4.92 mmol) and3-((S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide(2.6 g, 4.74 mmol) as a white solid.

(A) MS (m/z): 619.1 (M+73). ¹H NMR (CDCl₃, 400 MHz) δ 7.49 (s, 2H), 7.42(s, 1H), 6.56 (d, J=4.4 Hz 1H), 6.03 (s, 1H), 4.50-4.44 (m, 1H),4.06-4.02 (d, J=16 Hz, 1H), 3.69-3.65 (d, J=16 Hz, 1H), 3.48-3.43 (m,2H), 3.03-2.98 (m, 5H), 2.11-2.00 (m, 1H), 1.78 (s, 4H).

(B) MS (m/z): 619.1 (M+73). ¹H NMR (CDCl₃, 400 MHz) δ 7.49 (m, 2H), 7.41(m, 1H), 6.77-6.73 (m, 1H), 6.38-6.31 (m, 1H), 4.51-4.45 (m, 1H),4.05-4.01 (d, J=16 Hz, 1H), 3.71-3.67 (d, J=16 Hz, 1H), 3.49-3.39 (m,2H), 3.00-2.85 (m, 5H), 2.04-2.03 (m, 1H), 1.74 (s, 4H).

Preparation 883-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carbonylchloride

Stir a mixture of3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylicacid (600 mg, 1.2 mmol), 2 drops DMF in oxalyl dichloride (5 mL) atambient temperature for 3 hours. Remove the solvent under vacuum toafford3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carbonylchloride as a yellow solid (615 mg, 98%).

The following compound is prepared essentially by the method ofPreparation 88.

Prep. No. Chemical name Structure Physical data 893-[5-(3,4,5-Trichloro- thiophen-2-yl)-5-tri- fluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7- tetrahydro-benzo[c]thio- phene-1-carbonylchloride

EXAMPLE 90N-(4-carbamoylphenyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide

Stir a mixture of3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carbonylchloride (48 mg, 0.1 mmol) and 4-aminobenzamide (27 mg, 0.2 mmo) inpyridine (3 mL) at ambient temperature overnight. After removal solventunder vacuum, purify the residue by preparative HPLC to affordN-(4-carbamoylphenyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamideas a white solid (36 mg, 62.0%). MS (m/z): 582.1 (M+1). ¹H NMR (CDCl₃,400 MHz) δ 7.84 (d, J=8.4 Hz, 2H), 7.65-7.63 (m, 3H), 7.49 (s, 2H), 7.44(s, 1H), 6.03 (s, 1H), 5.61 (s, 1H), 4.09-4.05 (d, J=16 Hz, 1H),3.72-3.68 (d, J=16 Hz, 1H), 3.07 (s, 2H), 2.94 (s, 2H), 1.76 (s, 4H).

The following compound is prepared essentially by the method of Example90.

Ex. No. Chemical name Structure Physical data 913-[5-(3,4,5-Trichloro-thio- phen-2-yl)-5-trifluoro- methyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7- tetrahydro-benzo[c]thio- phene-1-carboxylic acid(3-carbamoyl-thiophen- 2-yl)-amide

MS (m/z): 628 (M + 1); ¹H NMR (400 MHz, DMSO-d₆,) δ 8.08-8.02 (m, 1H),7.81-7.78 (m, 1H), 4.58-4.43 (t, 2H), 3.13-2.84 (m, 4H), 1.79-1.64 (m,4H).

Preparation 922-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamido)aceticacid

Stir a mixture of methyl2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamido)acetate(534 mg, 1.0 mmol) and LiOH—H₂O (168 mg, 4.0 mmol) in MeOH (20 mL) andwater (5 mL) at room temperature for overnight. After removal of organicsolvent under vacuum, dilute the residue with ice water (10 mL). Acidifythe aqueous mixture with conc. HCl to pH=1, and extract the resultantmixture with EtOAc (15 mL×3). The combined organic layers are washedbrine, dried over anhydrous Na₂SO₄ and concentrated under vacuum. Purifythe residue by silica gel chromatograph (PE:EtOAc 1:1) to afford2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamido)aceticacid as a pale yellow solid (427 mg, 82.0%). MS (m/z): 521 (M+1).

The following compound is prepared essentially by the method ofPreparation 92.

Prep. No. Chemical name Structure Physical data 93({3-[5-(3,4,5-Trichloro- thiophen-2-yl)-5-tri- fluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7- tetrahydro-benzo[c]thio- phene-1-carbonyl}-amino)-acetic acid

MS (m/z): 561 (M + 1).

EXAMPLE 94N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide

Stir a mixture of2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamido)aceticacid (230 mg, 0.44 mmol), HATU (251 mg, 0.66 mmol) and NEt₃ (133 mg,1.32 mmol) in DCM (5 mL) at room temperature for 15 min, followed byaddition of 2-aminoacetonitrile hydrochloride (61 mg, 0.65 mmol). Stirthe reaction mixture at room temperature for additional 1.5 hour. Dilutethe reaction mixture with water (20 mL) and extract with DCM (20 mL×3).The combined organic layers are washed with brine, dried over anhydrousNa₂SO₄ and concentrated under vacuum. Purify the residue by preparativeHPLC to affordN-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamideas a white solid (110 mg, 44.7%). MS (m/z): 559.1 (M+1). ¹H NMR(DMSO-d₆, 400 MHz) δ 8.64 (t, J=5.6 Hz, 1H), 8.22 (t, J=5.6 Hz, 1H),7.81-7.80 (m 1H), 7.68 (s, 2H), 4.35-4.22 (m, 2H), 4.16-4.15 (m, 2H),3.88-3.86 (m, 2H), 2.94-2.86 (m, 4H), 1.70-1.69 (m, 4H).

The following compounds are prepared essentially by the method ofExample 94.

Ex. No. Chemical name Structure Physical data 95 3-(5-(3,5-dichloro-phenyl)-5-(trifluoromethyl)- 4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop- 2-ynylamino)ethyl)- 4,5,6,7-tetrahydro-benzo[c]thiophene-1- carboxamide

MS (m/z): 558 (M + 1); ¹H NMR (CDCl₃, 400 MHz) δ 7.49-7.42 (m, 3H), 6.85(br, 1H), 6.72 (br, 1H), 4.17-4.03 (m, 5H), 3.68 (d, J = 17.2 Hz, 1H),3.00-2.90 (m, 4H), 2.25 (s, 1H), 1.79 (br, 4H). 96 N-(2-(cyanomethyl-amino)-2-oxoethyl)-3-(5- (3,4,5-trichlorothiophen-2-yl)-5-(trifluoromethyl)- 4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydro- benzo[c]thiophene-1- carboxamide

MS (m/z): 599 (M + 1); ¹H NMR (CDCl₃, 400 MHz) δ 4.28-4.18 (m, 4H),4.10-4.07 (m, 2H), 3.04-2.87 (m, 4H), 1.88-1.73 (m, 4H).

Preparation 201 4-chlorobenzo[b]thiophene-2-carboxylic acid

Stir a mixture of methyl 4-chlorobenzo[b]thiophene-2-carboxylate (1.0 g,4.44 mmol) and LiOH—H₂O (0.56 g, 13.3 mmol) in MeOH (30 mL) and water(10 mL) at room temperature overnight. Concentrate the reaction mixtureunder vacuum and then dilute the residue with ice water (20 mL). Acidifythe aqueous mixture with conc. HCl solution to pH=1. Extract theresultant mixture with EtOAc (15 mL×3). The combined organic layers arewashed with brine, dried over anhydrous Na₂SO₄ and evaporate undervacuum to afford 4-chlorobenzo[b]thiophene-2-carboxylic acid as a whitesolid (0.94 g, 100%). ¹H NMR (400 MHz, CDCl₃) δ 8.10-8.02 (m, 2H),7.61-7.51 (m, 2H)

The following compounds are prepared essentially by the method ofPreparation 201.

Prep Physical No. Chemical name Structure data 202 Thieno[2,3-c]pyridine-2- carboxylic acid

MS (m/z): 180 (M + 1) 203 5-Bromo- thieno[2,3- b]pyridine-2- carboxylicacid

MS (m/z): 260 (M + 1).

Preparation 2044-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide

Stir a mixture of 4-chlorobenzo[b]thiophene-2-carboxylic acid (0.94 g,4.44 mmol), N,O-dimethylhydroxylamine hydrochloride (0.86 g, 8.87 mmol),DCC (1.1 g, 5.32 mmol) and DIEA (1.43 g, 1.9 mL, 11.08 mmol) in DCM (8mL) at ambient temperature for 2 hours. Filter the reaction mixture andthe filtrate is washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. Purify the residue by column chromatographyon silica gel eluting with PE: EtOAc (5:1 to 3:1) to afford4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide as whitesolid (0.85 g, 75.2%). ¹H NMR (400 MHz, CDCl₃) δ 8.10-8.02 (m, 2H),7.61-7.51 (m, 2H), 3.84-3.79 (s, 3H), 3.37-3.35 (s, 3H).

The following compound is prepared essentially by the method ofPreparation 204.

Prep. Chemical Physical No. name Structure data 205 N-methoxy- N-methyl-thieno[2,3- c]pyridine- 2-carbox- amide

MS (m/z): 223 (M + 1). 206 5-bromo-N- methoxy- N-methyl- thieno[2,3-b]pyridine-2- carboxamide

MS (m/z): 301 (M + 1).

Preparation 207 1-(4-chlorobenzo[b]thiophen-2-yl)ethanone

Add a solution of CH₃MgBr (3 M in THF, 1.7 ml, 4.99 mmol) to asuspension of 4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide(0.85 g, 3.33 mmol) in dry THF (10 mL) at 0° C. Then stir the mixturefor overnight at ambient temperature. Quench the reaction with saturatedNH₄Cl aqueous solution (15 mL) and extract the aqueous mixture withEtOAc (10 mL×3). The combined organic layers are washed with brine,dried over anhydrous Na₂SO₄ and concentrated under vacuum. Purify theresidue by silica gel chromatograph (PE:EtOAc=6:1) to afford1-(4-chlorobenzo[b]thiophen-2-yl)ethanone as white solid (0.6 g, 86.9%).¹H NMR (400 MHz, CDCl₃) δ 8.10-8.07 (s, 1H), 7.75 (d, J=5.2, 1H),7.47-7.36 (m, 2H), 2.72-2.68 (s, 3H).

The following compounds are prepared essentially by the method ofPreparation 207.

Prep Chemical Physical No. name Structure data 208 1-Thieno[2,3-c]pyridin- 2-yl-ethanone

MS (m/z): 178 (M + 1). 209 1-(5-Bromo- thieno[2,3- b]pyridin-2-yl)-ethanone

MS (m/z): 258 (M + 1). 210 1-Thieno[2,3- b]pyridin- 2-yl-ethanone

MS (m/z): 178 (M + 1)

Preparation 2111-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one

Add a solution of LiHMDS (1 M in THF, 4.3 ml, 4.31 mmol) to a mixture of1-(4-chlorobenzo[b]thiophen-2-yl)ethanone (0.6 g, 2.87 mmol) in dry THF(10 mL) at −78° C. under N₂. After stirring 1.5 hour at −78° C., add1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (836 mg, 3.44 mmol) tothe reaction mixture and stir the resultant mixture for additional 2hours. Quench the reaction with saturated NH₄Cl solution and extract theaqueous mixture with EtOAc (10 mL×3). The combined organic layers arewashed with brine, dried over anhydrous Na₂SO₄ and concentrated undervacuum afford crude1-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-oneas brown solid (1.1 g, 84.6%). ¹H NMR (400 MHz, CDCl₃) δ 8.10-8.07 (s,1H), 7.75 (d, J=5.2, 1H), 7.47-7.36 (m, 2H), 2.72-2.68 (s, 3H).

The following compounds are prepared essentially by the method ofPreparation 211.

Prep. No. Chemical name Structure Physical data 2123-(3,5-Dichloro-phenyl)-4,4,4- trifluoro-3-hydroxy-1-thieno[2,3-c]pyridin-2- yl-butan-1-one

MS (m/z): 418 (M − 1) 213 3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-hydroxy-1-(5- bromo-thieno[2,3-b]pyridin- 2-yl)-butan-1-one

MS (m/z): 498 (M − 1). 214 3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-hydroxy-1- thieno[2,3-b]pyridin-2- yl-butan-1-one

MS (m/z): 418 (M − 1). 215 1-(benzo[d]thiazol-2-yl)-3-(3,5-dichlorophenyl)-4,4,4- trifluoro-3-hydroxybutan- 1-one

MS (m/z): 418 (M − 1). 216 3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxy-1-(3- methylbenzo[b]thiophen-2- yl)butan-1-one

MS (m/z): 431 (M − 1). 217 3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxy-1-(5- methylbenzo[b]thiophen-2- yl)butan-1-one

MS (m/z): 431 (M − 1). 218 1-(5-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)- 4,4,4-trifluoro-3-hydroxy- butan-1-one

MS (m/z): 451 (M − 1). 219 1-(benzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4- trifluoro-3-hydroxybutan- 1-one

MS (m/z): 417 (M − 1).

Preparation 2201-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-en-1-one

Stir a mixture of1-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one(1.1 g, crude, 2.43 mmol), SOCl₂ (1.16 g, 0.7 mL, 9.43 mmol) andpyridine (384 mg, 0.4 mL, 4.86 mmol) in anhydrous DCM (10 mL) at ambienttemperature for overnight. Dilute the mixture with saturated NH₄Clsolution and extract the aqueous mixture with DCM (10 mL×3). Thecombined organic layers are washed with brine, dried over anhydrousNa₂SO₄ and concentrated under vacuum to afford crude1-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-en-1-oneas brown solid (1.05 g, 100%). ¹H NMR (400 MHz, CDCl₃) 68.12-8.10 (s,1H), 7.69-7.64 (m, 1H), 7.47-7.44 (m, 2H), 7.38-7.35 (m, 2H), 7.27-7.24(m, 1H), 6.96-6.92 (s, 1H).

The following compounds are prepared essentially by the method ofPreparation 220.

Prep. No. Chemical name Structure Physical data 2213-(3,5-Dichloro-phenyl)- 4,4,4-trifluoro-1- thieno[2,3-c]pyridin-2-yl-but-2-en-1-one

MS (m/z): 400 (M − 1). 222 3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-1-(5- bromo-thieno[2,3- b]pyridin-2-yl)-but- 2-en-1-one

MS (m/z): 480 (M − 1). 223 3-(3,5-Dichloro-phenyl)- 4,4,4-trifluoro-1-thieno[2,3-b]pyridin-2- yl-but-2-en-1-one

MS (m/z): 400 (M − 1). 224 1-(benzo[b]thiophen-2- yl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro- but-2-en-1-one

MS (m/z): 399 225 1-(benzo[d]thiazol-2- yl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro- but-2-en-1-one

MS (m/z): 400 226 3-(3,5-dichlorophenyl)- 4,4,4-trifluoro-1-(3- methyl-benzo[b]thiophen- 2-yl)but-2-en-1-one

MS (m/z): 413 227 3-(3,5-dichlorophenyl)- 4,4,4-trifluoro-1-(5- methyl-benzo[b]thiophen- 2-yl)but-2-en-1-one

MS (m/z): 413 228 1-(5-chloro- benzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)- 4,4,4-trifluorobut- 2-en-1-one

MS (m/z): 433

EXAMPLE 2293-(4-chlorobenzo[b]thiophen-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

Stir a mixture of1-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-en-1-one(1.05 g, crude, 2.43 mmol), NaOH (389 mg, 9.72 mmol) and NH₂OH—HCl (335mg, 4.8 mmol) in MeOH mL) and water (8 mL) at ambient temperature for 4hours. After removal of solvent under vacuum, dilute the residue withice water (20 mL). Extract the aqueous mixture with EtOAc (15 mL×3). Thecombined organic layers are washed with brine, dried over anhydrousNa₂SO₄ and concentrated under vacuum. Purify the residue by preparativeHPLC to afford3-(4-chlorobenzo[b]thiophen-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazoleas white solid (305 mg, 28.1%). MS (m/z): 450 (M+1). ¹H NMR (400 MHz,CDCl₃) δδ 7.74 (d, J=8.0, 1H), 7.64-7.60 (s, 1H), 7.57-7.53 (m, 2H),7.47-7.43 (m, 1H), 7.40-7.32.

The following compounds are prepared essentially by the method ofExample 229.

Ex. No. Chemical name Structure Physical data 230 2-[5-(3,5-Dichloro-phenyl)-5-trifluoro- methyl-4,5-dihydro- isoxazol-3-yl]-thieno[2,3-c]pyridine

MS (m/z): 417 (M + 1). ¹H NMR (400 MHz, CDCl₃) δ 9.17 (s, 1H), 8.55-8.57(d, J = 5.6, 1H), 7.68-7.69 (d, J₁ = 5.6, J₂ = 1.2, 1H), 7.51-7.52 (d, J= 1.2, 2H), 7.49 (S, 1H), 7.45-7.46 (t, J = 3.6, 1H), 4.17-4.21 (d, J =16.8, 1H), 3.79-3.83 (d, J = 16.8, 1H). 231 5-Bromo-2-[5-(3,5-dichloro-phenyl)-5- trifluoromethyl-4,5- dihydro-isoxazol-3-yl]-thieno[2,3- b]pyridine

MS (m/z): 497 (M + 1). 1H NMR (400 MHz, CDCl₃) δ 8.65-8.66 (d, J = 1.6,1H), 8.18-8.19 (d, J = 2.0, 1H), 7.51 (S, 2H), 7.45-7.46 (d, J = 1.6,1H), 7.32 (S, 1H), 4.13-4.17 (d, J = 16.8, 1H), 3.75-3.79 (d, J = 16.8,1H). 232 2-[5-(3,5-Dichloro- phenyl)-5-trifluoro- methyl-4,5-dihydro-isoxazol-3-yl]- thieno[2,3-b]pyridine

MS (m/z): 417 (M + 1). ¹H NMR (400 MHz, CDCl₃) δ 8.62-8.64 (d, J₁ = 4.4,J₂ = 1.6, 1H), 8.05-8.07 (d, J₁ = 8.0, J₂ = 1.6, 1H), 7.51-7.52 (d, J =1.2, 2H), 7.44-7.45 (t, J = 3.6, 1H), 7.41 (s, 1H), 7.33-7.36 (m, 1H),4.15-4.19 (d, J = 16.8, 1H), 3.77-3.81 (d, J = 16.8, 1H). 2333-(benzo[b]thiophen- 2-yl)-5-(3,5-dichloro- phenyl)-5-(trifluoro-methyl)-4,5- dihydroisoxazole

MS (m/z): 416 (M + 1). 1H NMR (400 MHz, CDCl₃) δ 7.84 (d, J = 8.0, 1H),7.82 (d, J = 8.0, 1H), 7.55-7.50 (m, 2H), 7.48-7.34 (m, 4H), 4.20 (d, J= 16.8, 1H), 3.80 (d, J = 17.6, 1H). 234 3-(benzo[d]thiazol-2-yl)-5-(3,5-dichloro- phenyl)-5-(trifluoro- methyl)-4,5-dihydro-isoxazole

MS (m/z): 417 (M + 1). 1H NMR (400 MHz, CDCl₃) δ 8.07 (d, J = 7.2, 1H),7.93 (d, J = 7.2, 1H), 7.58-7.47 (m, 5H), 4.37 (d, J = 18.0, 1H), 4.00(d, J = 18.0, 1H) 235 5-(3,5-dichloro- phenyl)-3-(3-methyl-benzo[b]thiophen- 2-yl)-5-(trifluoro- methyl)-4,5-dihydro- isoxazole

MS (m/z): 430 (M + 1). 1H NMR (400 MHz, CDCl₃) δ 7.83-7.78 (m, 2H), 7.53(s, 2H), 7.53-7.43 (m, 3H), 4.17 (d, J = 16.8, 1H), 3.79 (d, J = 16.8,1H), 2.67 (s, 3H). 236 5-(3,5-dichloro- phenyl)-3-(5-methyl-benzo[b]thiophen- 2-yl)-5-(trifluoro- methyl)-4,5-dihydro- isoxazole

MS (m/z): 430 (M + 1). 1H NMR (400 MHz, CDCl₃) δ 7.71 (d, J = 8.0, 1H),7.57 (s, 1H), 7.53 (s, 2H), 7.43 (t, J = 3.2, 1H), 7.36 (d, J = 7.0,1H), 7.24 (d, J = 7.0, 1H), 4.17 (d, J = 16.8, 1H), 3.78 (d, J = 16.8,1H), 2.47 (s, 3H). 237 3-(5-chloro- benzo[b]thiophen-2-yl)-5-(3,5-dichloro- phenyl)-5-(trifluoro- methyl)-4,5-dihydro-isoxazole

MS (m/z): 450 (M + 1). 1H NMR (400 MHz, CDCl₃) δ 7.76-7.75 (m, 2H), 7.51(s, 2H), 7.45-7.44 (m, 1H), 7.40-7.38 (m, 2H), 4.18 (d, J = 16.8, 1H),3.78 (d, J = 17.6, 1H).

Preparation 238 methyl2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thieno[2,3-b]pyridine-5-carboxylate

Stir a mixture of5-bromo-2-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-thieno[2,3-b]pyridine(494 mg, 1 mmol), Pd(dppf)Cl₂ (100 mg) and triethyl amine (1 mL) inanhydrous THF (10 mL) and methanol (5 mL) under carbon monoxide (50 psi)at 70° C. for 10 h. After removal of solvent under vacuum, purify theresidue with silica gel chromatography (eluting with 10% ethyl acetatein petroleum ether) to afford methyl2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thieno[2,3-b]pyridine-5-carboxylateas a white solid (210 mg, 44.18%). MS (m/z): 475 (M+1).

Preparation 2392-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-thieno[2,3-b]pyridine-5-carboxylicacid

Add a solution of LiOH—H₂O (76 mg, 2 mmol) in water (0.5 mL) to asolution of methyl2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thieno[2,3-b]pyridine-5-carboxylate (237 mg, 0.5 mmol) in THF (3 mL). Stir the mixture attemperature for 12 hours. After addition of 10 mL of water, acidify themixture with concentrated HCl to PH=6˜7. Extract the resultant mixturewith ethyl acetate (3×10 mL). The combined organic layers are washedbrine, dried over anhydrous Na₂SO₄ and concentrated under vacuum toafford2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]thieno[2,3-b]pyridine-5-carboxylicacid as pale yellow solid (170 mg, 73.9%), which is used in next stepwithout further purification. MS (m/z): 461 (M+1).

EXAMPLE 2402-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)thieno[2,3-b]pyridine-5-carboxamide

Stir a mixture of 2-Amino-N-(2,2,2-trifluoro-ethyl)-acetamide (156 mg, 1mmol),2-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-thieno[2,3-b]pyridine-5-carboxylicacid (160 mg, 0.24 mmol), HATU (150 mg, 0.39 mmol) and DIPEA (0.2 mL) atroom temperature for 10 hours. After removal of solvent, purify themixture by preparative-HPLC to afford2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)thieno[2,3-b]pyridine-5-carboxamideas a white solid (50 mg, 34.78%). MS (m/z): 599 (M+1). ¹H NMR (400 MHz,CDCl₃) δ 9.02 (s, 1H), 8.51 (s, 1H), 7.52 (s, 2H), 7.44-7.41 (m, 2H),7.22 (s, 1H), 6.64 (s, 1H), 4.27 (d, J=5.2, 2H), 4.17 (d, J=16.8, 1H),4.04-3.95 (m, 2H), 3.80 (d, J=16.08, 1H).

The following compound is prepared essentially by the method of Example240.

Ex. No. Chemical name Structure Physical data 241 2-(5-(3,5-dichloro-phenyl)-5-(trifluoro- methyl)-4,5-dihydro- isoxazol-3-yl)-N-((R)-2-oxopyrrolidin- 3-yl)thieno[2,3- b]pyridine-5- carboxamide

MS (m/z): 543 (M + 1). ¹H NMR (400 MHz, CDCl₃) δ 9.01 (s, 1H), 8.49 (s,1H), 7.54 (s, 2H), 7.44-7.40 (m, 2H), 7.15 (S, 1H), 5.89 (s, 1H), 4.60(s, 1H), 4.18 (d, J = 16.8, 1H), 3.80 (d, J = 16.8, 1H), 3.51-3.48 (m,2H), 3.00-2.93 (m, 1H), 2.14-2.08 (m, 1H)

EXAMPLE 2423-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide

Stir a mixture of3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid (1.0 g, 2.14 mmol), N,N-diisopropylethylamine (827 mg, 6.41 mmol),2-amino-N-(2,2,2-trifluoroethyl) acetamide hydrochloride (658 mg, 2.56mmol) and HATU (1.2 g, 3.2 mmol) in CH₂Cl₂ (10 mL) at room temperaturefor 2 hours. The reaction mixture is diluted with CH₂Cl₂ (50 mL) and iswashed with water (10 mL×3) and brine. Then the organic layer is driedover anhydrous Na₂SO₄ and is concentrated under vacuum. Purify theresidue by preparative HPLC to afford3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamideas a white solid (1.1 g, 84.6%). MS (m/z): 606.0 (M+1).

EXAMPLE 243(S)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide

1 g of3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamideis separated by SFC to give(S)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide(400 mg, 80% yield, 100% ee).

¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, J=6.0, 2 H), 6.92 (t, J=6.4, 1 H),6.76 (t, J=4.8, 1 H), 4.21 (d, J=4.8, 2 H), 3.98 (m, 3H), 3.61 (d,J=16.8, 1 H), 2.97 (t, J=7.6, 2 H), 2.89 (t, J=7.6, 2 H), 2.55 (m, 2H).MS (m/z): 606.0 (M+1).

SFC analysis condition: Column: Chiralcel AD-H 250×4.6 mm I.D., 5 um.Mobile phase: ethanol in CO₂ from 5% to 40% over 3 minutes. Flow rate:2.35 mL/min. Wavelength: 220 nm. The S-isomer elutes at 1.4 minutes. SFCseparation condition: Instrument: Thar SFC 80; Column: AD 250 mm*20 mm,20 um; Mobile phase: A: Supercritical CO₂, B: MeOH (0.05% NH₃H₂O),A:B=45:55 at 80 ml/min; Column Temp: 38° C.; Nozzle Pressure: 100 Bar;Nozzle Temp: 60° C.; Evaporator Temp: 20° C.; Trimmer Temp: 25° C.;Wavelength: 220 nm

EXAMPLE 2443-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid [(2,2-difluoro-ethylcarbamoyl)-methyl]-amide

A) Synthesis of 2-acetoxy-propionic acid

Reflux a mixture of 2-hydroxy-propionic acid (480 ml, 85% in water) andsulfuric acid (2 mL) in acetic acid (2500 mL) and toluene (300 mL) forovernight. After removal of solvent under vacuum, purify the residue bydistillation to give 2-acetoxy-propionic acid (550 g, 92%) as colorlessoil. ¹H NMR (CDCl₃, 400 MHz): δ 9.27 (brs, 1H), 5.10 (m, 1H), 2.13 (s,3H), 1.53 (d, J=7.2, 3H).

B) Synthesis of 1-chloro-1-oxopropan-2-yl acetate

Stir a mixture of 2-acetoxy-propionic acid (550 g, 4.16 mol) in oxalylchloride (500 mL) at room temperature for overnight. After removal ofoxalyl chloride under vacuum, ˜700 g crude product is obtained(quantitative yield crude), which is used directly in the next step. ¹HNMR (CDCl₃, 400 MHz): δ 5.16 (m, 1H), 2.13 (s, 3H), 1.58 (d, J=7.2, 3H).

C) Synthesis of 1-cyclopentenylpyrrolidine

Reflux a mixture of cyclopentanone (600 g, 7.14 mol), pyrrolidine (550g, 4.68 mol) and toluene-4-sulfonic acid (5.0 g) in toluene (3 L) for 4hours. After removal of solvent under vacuum, purify the residue bydistillation carefully to give 1-cyclopent-1-enyl-pyrrolidineascolorless oil (898 g, 6.55 mol, 91.8%). ¹H NMR (CDCl₃, 400 MHz): δ 4.04(m, 1H), 3.06 (m, 4H), 2.39 (m, 4H), 1.85 (m, 6H).

D) Synthesis of 1-oxo-1-(2-(pyrrolidin-1-yl)cyclopent-1-enyl)propan-2-ylacetate

Add dropwise a solution of 1-chloro-1-oxopropan-2-yl acetate (600 g,3.98 mol) in toluene (1200 mL) to a solution of1-cyclopent-1-enyl-pyrrolidine (546.7 g, 3.98 mol) and triethyl amine(483.9 g, 4.78 mol) in toluene (2400 mL). Reflux the mixture forovernight. Filter the mixture and concentrate the filtration to givecrude 1-oxo-1-(2-(pyrrolidin-1-yl)cyclopent-1-enyl)propan-2-yl acetate(952 g), which is used in next step without further purification. ¹H NMR(CDCl₃, 400 MHz): δ 5.27 (m, 1H), 3.56 (m, 2H), 3.16 (m, 2H), 2.83 (m,1H), 2.58 (m, 3H), 2.10 (s, 3H), 1.93 (m, 2H), 1.82 (m, 4H), 1.36 (d,J=7.2, 3H).

E) Synthesis of 1-oxo-1-(2-oxocyclopentyl)propan-2-yl acetate

Stir a mixture of1-oxo-1-(2-(pyrrolidin-1-yl)cyclopent-1-enyl)propan-2-yl acetate (952.0g), acetic acid (1500 mL) and water (1500 mL) in tetrahydrofuran (3000mL) at room temperature for 2 days. Dilute the mixture with water (1200mL) and dichloromethane (1200 mL). The organic layer is washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under vacuum. Purifythe residue by silica gel chromatograph (eluting with 3% to 10% ethylacetate in petroleum ether) to give1-oxo-1-(2-oxocyclopentyl)propan-2-yl acetate as oil (573.4 g, 2.89 mol,72.6% for 2 steps).

F) Synthesis of 1-chloro-1-(2-oxocyclopentylidene)propan-2-yl acetate

A mixture of 1-oxo-1-(2-oxocyclopentyl)propan-2-yl acetate (8.0 g, 0.04mol) and tributylphosphane (13.9 g, 0.069 mol) in CCl₄ (100 mL) at 60°C. overnight. After removal of solvent, the residue is purified bysilica gel column (eluting with 1% to 2.5% ethyl acetate in petroleumether) to give a mixture of1-chloro-1-(2-oxocyclopentylidene)propan-2-yl acetate and1-(2-chlorocyclopent-1-enyl)-1-oxopropan-2-yl acetate (5.47 g, 6:1 basedon HNMR) as yellow oil.

G) Synthesis of methyl3-(1-hydroxyethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylate

Add sodium hydride (60% in mineral oil, 2.12 g, 0.053 mol) to a solutionof mercapto-acetic acid methyl ester (2.8 g, 0.026 mol) intetrahydrofuran (100 mL) at −10° C.˜0° C. and stirred the mixture at−10° C.˜0° C. for 1 hour. Then add a mixture of1-chloro-1-(2-oxocyclopentylidene)propan-2-yl acetate and1-(2-chlorocyclopent-1-enyl)-1-oxopropan-2-yl acetate (5.47 g, 0.025mol, 6:1) in tetrahydrofuran (15 mL) at 0° C. After stirring at 0° C.for overnight, dilute the reaction mixture with water and extract withethyl acetate. The combined organic layers are washed with brine, driedover anhydrous Na₂SO₄ and concentrated. The residue and K₂CO₃ (6.9 g,0.05 mol) in MeOH (20 mL) is heated at 50° C. overnight. The solvent isremoved. The residue is purified by silica gel chromatograph (elutingwith 2.5% to 10% ethyl acetate in petroleum ether) to give3-(1-hydroxy-ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid methyl ester (3.2 g, 14.1 mmol, 35.6% for 2 steps) as yellow oil.¹H NMR (CDCl₃, 400 MHz): δ 5.03 (m, 1H), 3.83 (m, 3H), 2.88 (m, 2H),2.66 (m, 2H), 2.38 (m, 2H), 2.12 (s, 1H), 1.54 (d, J=7.2, 3H).

H) Synthesis of methyl3-acetyl-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylate

Reflux a mixture of3-(1-Hydroxy-ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid methyl ester (3.2 g, 0.0141 mol) and manganese dioxide (10.8 g,0.124 mol) in dichloromethane for 2 hours. Filter the hot reactionmixture solution and concentrate the filtration under vacuum. Purify theresidue by silica gel chromatograph (eluting with 2% to 10% ethylacetate in petroleum ether) to give3-acetyl-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methylester as white solid (3.0 g, 13.39 mmol, 94.5%). ¹H NMR (CDCl₃, 400MHz): δ 3.88 (s, 3H), 2.96 (m, 4H), 2.50 (s, 3H), 2.45 (m, 2H).

I) Synthesis of3-[3-(3,5-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxy-butyryl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid methyl ester

Add a solution of LiHDMS (1M in THF, 75 mL, 75 mmol) to a suspension of3-acetyl-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methylester (14.0 g, 62.5 mmol) in dry THF (200 mL) at −78° C. under N₂. Afterstirring at room temperature for 1.5 h, add1-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone (17.9 g, 68.7mmol) in dry THF (100 mL) to the reaction mixture and stir the resultantmixture at the same temperature for additional 2 hours. Quench thereaction with saturated NH₄Cl aqueous solution. Extract the aqueousmixture with EtOAc (100 mL×3). The combined organic layers are washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum.Purify the residue by silica gel chromatograph (PE:EtOAc 15:1) to afford3-[3-(3,5-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxy-butyryl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid methyl ester as an orange solid (27 g, 89.3%). MS (m/z): 486 (M+1).

J) Synthesis of3-[3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid methyl ester

Stir a mixture of3-[3-(3,5-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxyl-butyryl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid methyl ester (26 g, 53.7 mmol), SOCl₂ (12.7 g, 7.8 mL, 0.107 mmol)and pyridine (42.3 g, 0.537 mmol) in anhydrous DCM (300 mL) at roomtemperature for 3 hours. Concentrate the mixture under vacuum. Purifythe residue by silica gel chromatograph (PE:EtOAc 12:1) to afford3-[3-(3,5-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid methyl ester as a pale yellow solid (25 g, 100%). (m/z): 467 (M+1).

K) Synthesis of3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid methyl ester

Stir a mixture of3-[3-(3,5-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid methyl ester (25 g, 53.6 mmol), NaOH (8.6 g, 0.214 mol) andNH₂OH—HCl (7.4 g, 0.107 mmol) in water (100 mL) and THF (200 mL) at roomtemperature for overnight. After removal of the solvent under vacuum,the solution is diluted with water and extracted with EtOAc (200 mL×3).The combined organic layer is washed with brine, dried over anhydrousNa2SO4 and concentrated by vacuum to afford3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid methyl ester as a white solid (26 g), which is used directly in thenext step without purification. MS (m/z): 483 (M+1).

L) Synthesis of3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid

Stir a mixture of3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid methyl ester (26 g, 54.1 mmol) and LiOH—H₂O (4.54 g, 0.108 mmol) inwater (200 mL) and THF (400 mL) at 50° C. for 0.5 hour. After removal oforganic solvent under vacuum, dilute the residue with ice water (100mL). Acidify the aqueous mixture with conc. HCl to pH=1, and extract theresultant mixture with EtOAc (200 mL×3). Purify the residue by silicagel chromatograph (EtOAc:MeOH 6:1) to afford3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid as a white solid (23 g, 91.7% for 2 steps). MS (m/z): 468 (M+1).

M) Synthesis of [(2,2-difluoro-ethylcarbamoyl)-methyl]-carbamic acidtert-butyl ester

To a solution of compound tert-butoxycarbonylamino acetic acid (19.6 g,0.1 mol) in dichloromethane (200 mL) is added N,N-diisopropylethylamine(13.2 g, 0.1 mol), 2,2-difluoroethylamine (10 g, 0.1 mol) and HATU (23g, 0.17 mol), after the addition the mixture is stirred at roomtemperature for 1 hour. After being detected by TLC and LCMS, thereaction mixture is diluted with dichloromethane, then the solution iswashed with water and brine, dried over anhydrous Na₂SO₄, filtered,concentrated and the residue is dried in vacuum to give 30 g crudeproduct, which is used directly in next step.

O) Synthesis of 2-amino-N-(2,2-difluoro-ethyl) acetamide hydrochlorideP)

To a solution of compound[(2,2-difluoro-ethylcarbamoyl)-methyl]-carbamic acid tert-butyl ester(30 g crude product, 0.13 mol) in acetic acid ethyl ester (100 mL) isadded 4 M HCl (100 mL, 4 mol/L in acetic acid ethyl ester) dropwiseunder ice-water bath. After the addition the reaction mixture is warmedto room temperature and stirred for overnight. The precipitate iscollected and dried in vacuum to give desired product (20 g, 93% for twosteps) as a white solid. 1H NMR (DMSO-d₆, 400 MHz): δ 8.91 (t, J=6.0, 1H), 8.25 (brs, 3H), 6.21-5.91 (m, 1H), 3.64-3.53 (m, 4H).

O) Synthesis of3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid [(2,2-difluoro-ethylcarbamoyl)-methyl]-amide

To a solution of compound3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[e]thiophene-1-carboxylicacid (3 g, 6.4 mmol) in acetonitrile (30 mL) is addedN,N-diisopropylethylamine (2.5 g, 19 mmol),2-amino-N-(2,2-difluoro-ethyl)-acetamide hydrochloride (1.34 g, 7.7mmol) and HATU (3.7 g, 9.6 mmol), after the addition the mixture isstirred at room temperature for 1 hour. After being detected by TLC andLCMS, the reaction mixture is concentrated and the residue is purifiedby column chromatography to afford desired product (3 g, 88%). MS (m/z):588.1 (M+1).

EXAMPLE 245(S)-3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid [(2,2-difluoro-ethylcarbamoyl)-methyl]-amide

3 g of3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid [(2,2-difluoro-ethylcarbamoyl)-methyl]-amide is separated by SFCseparation to give desired product (1.4 g, 93%).

1H NMR (CDCl₃, 400 MHz): δ 7.56 (d, J=6.0, 2 H), 6.64 (brs, 1H), 6.40(brs, 1H), 6.03-5.73 (m, 1H), 4.15 (d, J=5.2, 2 H), 4.01 (d, J=17.2, 1H), 3.74-3.65 (m, 1H), 3.62 (d, J=17.2, 1 H), 2.97 (t, J=7.6, 2 H), 2.89(t, J=7.6, 2 H), 2.56 (m, 2H).

SFC conditions are as follows:

Instrument: Thar 350

Column: AD 250 mm*50 mm, 10 um

Mobile phase: A: Supercritical CO2, B: EtOH, A:B=60:40 at 240 ml/min

Column Temp: 38° C.

Nozzle Pressure: 100 Bar

Nozzle Temp: 60° C.

Evaporator Temp: 20° C.

Trimmer Temp: 25° C.

Wavelength: 220 nm

EXAMPLE 2463-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid [(2-fluoro-ethylcarbamoyl)-methyl]-amide

A) Synthesis of({3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carbonyl}-amino)-aceticacid methyl ester

To a solution of compound3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid (10.0 g, 21.4 mmol) in dichloromethane (100 mL) is addedtriethylamine (6.49 g, 64.2 mmol), glycine methyl ester hydrochloride(3.2 g, 25.7 mmol) and HATU (12.2 g, 32.1 mmol), after the addition themixture is stirred at room temperature for 1 hour. After being detectedby TLC and LCMS, the reaction mixture is diluted with dichloromethane,then the solution is washed with water and brine, dried over anhydrousNa₂SO₄, filtered, concentrated and the residue is dried in vacuum togive 11 g crude product, which is used directly in next step.

B) Synthesis of({3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carbonyl}-amino)-aceticacid

Stir a mixture of({3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carbonyl}-amino)-aceticacid methyl ester (11 g, 18.6 mmol) and LiOH—H₂O (1.56 g, 37.2 mmol) inTHF (100 mL) and water (50 mL) at room temperature for overnight. Afterbeing checked with TLC, the solvent is removed under vacuum, dilute theresidue with water (50 mL). Acidify the aqueous mixture with 2M HCl topH=3, and extract the resultant mixture with EtOAc (100 mL×3), thecombined organic layer is washed with brine, dried over anhydrous Na₂SO₄and concentrated under vacuum, the residue is purified by silica gelchromatograph (PE:EtOAc 1:1) to afford({3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carbonyl}-amino)-aceticacid as a white solid (10.2 g, 90.7% for two steps). MS (m/z): 525(M+1).

C) Synthesis of3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid [(2-fluoro-ethylcarbamoyl)-methyl]-amide

To a solution of compound({3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carbonyl}-amino)-aceticacid (100 mg, 0.19 mmol) in acetonitrile (5 mL) is addedN,N-diisopropylethylamine (49.3 mg, 0.38 mmol), 2-fluoro-ethylamine(14.4 mg, 0.23 mmol) and HATU (108.8 mg, 0.29 mmol), after finished themixture is stirred at room temperature for 1 hour. After being detectedby TLC and LCMS, the reaction mixture is concentrated and the residue ispurified by column chromatography to afford desired product (100 mg,92%). MS (m/z): 570.1 (M+1).

EXAMPLE 247(S)-3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid [(2-fluoro-ethylcarbamoyl)-methyl]-amide

100 mg of3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid [(2-fluoro-ethylcarbamoyl)-methyl]-amide is separated by SFCseparation to give desired product (40 mg, 80%).

1H NMR (CDCl₃, 400 MHz): δ 7.49 (d, J=6.0, 2 H), 6.64 (brs, 1H), 6.34(brs, 1H), 4.52 (t, J=4.8, 1 H), 4.40 (t, J=4.8, 1 H), 4.06 (d, J=4.4, 2H), 3.94 (d, J=17.2, 1 H), 3.63-3.52 (m, 3H), 2.90 (t, J=7.6, 2 H), 2.81(t, J=7.6, 2 H), 2.47 (m, 2H).

SFC conditions are as follows:

Instrument: Thar SFC 80

Column: AD 250 mm*20 mm, 20 um

Mobile phase: A: Supercritical CO2, B: EtOH (0.05% DEA), A:B=45:55 at 80ml/min

Column Temp: 38° C.

Nozzle Pressure: 100 Bar

Nozzle Temp: 60° C.

Evaporator Temp: 20° C.

Trimmer Temp: 25° C.

Wavelength: 220 nm

EXAMPLE 2483-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide

Stir a mixture of3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid (0.8 g, 1.7 mmol), N,N-diisopropylethylamine (663 mg, 5.1 mmol),2-amino-N-(prop-2-yn-1-yl) acetamide hydrochloride (305 mg, 2.0 mmol)and HATU (974 g, 2.6 mmol) in CH₂Cl₂ (10 mL) at room temperature for 2hours. The reaction mixture is diluted with CH₂Cl₂ (40 mL) and is washedwith water (10 mL×3) and brine. Then the organic layer is dried overanhydrous Na₂SO₄ and concentrated under vacuum. Purify the residue bypreparative HPLC to afford3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamideas a white solid (850 mg, 88.4%). MS (m/z): 584.1 (M+Na).

EXAMPLE 249(S)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide

850 mg of3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamideis separated by SFC to give(S)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide(400 mg, 94% yield, 99.7% cc).

¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, J=6.0, 2 H), 6.76 (t, J=4.8, 1 H),6.46 (t, J=4.8, 1 H), 4.14 (m, 4H), 4.03 (d, J=17.2, 1 H), 3.64 (d,J=17.2, 1 H), 2.99 (t, J=7.6, 2 H), 2.90 (t, J=7.6, 2 H), 2.56 (m, 2H),2.29 (t, J=2.8, 1 H). MS (m/z): 584.1 (M+Na)

SFC analysis condition: Column: Chiralcel AS-H 150×4.6 mm I.D., 5 um.Mobile phase: EtOH in CO₂ from 5% to 40% over 8 minutes. Flow rate: 3mL/min. Wavelength: 220 nm. The S-isomer elutes at 4.00 minutes.

Instrument: Thar SFC 200; Column: AS 250 mm*50 mm, 10 um; Mobile phase:A: Supercritical CO₂, B: EtOH, A:B=45:55 at 200 ml/min; Column Temp: 38°C.; Nozzle Pressure: 100 Bar; Nozzle Temp: 60° C.; Evaporator Temp: 20°C.; Trimmer Temp: 25° C.; Wavelength: 220 nm.

In Vitro Helminth Assay

Compounds may be evaluated against one or more life stages of helminthto measure anthelmintic activity. Compounds may be evaluated at a singleconcentration followed by serial dilution in order to determine minimaleffective concentration. Typically, worms are exposed to compounds in aliquid solution for a predetermined period of time. Activity is measuredthrough one or more variables, which may include an effect on wormmotility (e.g., moving versus non-moving) or viability (e.g., liveversus dead).

In Vivo Activity Against Nematodes

Compounds may be evaluated against one or more life stages of helminthinfestation in an animal to measure in vivo anthelmintic activity.Compounds may be evaluated a single dose, administered on a milligramper kilogram body weight basis, followed by dose titration in order todetermine minimal effective point dose. In a rodent anthelmintic model,for example, adult Mongolian gerbils (Meriones unguiculates) infectedwith one or more species of Strongylid nematode (e.g., Haemonchuscontortus and/or Trichostrongylus colubriformis) are dosed withcompounds, administered via oral gavage. Gerbils are necropsied andgastrointestinal tract worm burden is measured and compared tountreated, infected control gerbils to determine the degree ofanthelmintic activity. Similar testing may be conducted in higherspecies (e.g., dogs, cats, sheep, cattle) whereby nematode burden intreated animals is compared to burden in untreated, infected animals tomeasure the potency and duration of anthelmintic activity.

In Vitro Larval Immersion Microassay (LIM)

The larval immersion microassay may be conducted as described in White,et al., J. Med. Entomol. 41: 1034-1042 (2004). Briefly, experimentaltest articles are formulated in dimethylsulfoxide (DMSO) to prepare astock solution at a concentration of 10 mM. Using 96-well microtiterplates, an aliquot of the 10 mM sample is subsequently diluted in awater-based solution containing 1% ethanol and 0.2% Triton X-100, toobtain the desired concentration (typically 0.3 mM or lower) ofexperimental test article in a volume of 0.1 ml (minimum n=3 replicatesper compound or concentration). Approximately 30-50 Lone star ticklarvae (Amblyomma americanum) are submerged into each well containingexperimental test articles. After a 30 minute immersion period, larvaeare removed with a wide-bore pipette tip in 0.05 ml of fluid, dispensedinto a commercial paper tissue biopsy bag which is sealed at the topwith a plastic dialysis clip, inverted and allowed to air dry for 60minutes. Bags containing larvae are then incubated at approximately 27degrees Celsius and >90% relative humidity. After 24 hours, bags areopened, live and dead larvae are counted and percent larval mortality iscalculated as follows: % Efficacy=(# dead larvae)/(# total larvae)×100.

The following of the Examples exhibited efficacy, and at the level of≧80% efficacy when tested in this assay at 300 micromolar: 32, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 74,75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87b, 94, 95, 96, 230,231, 232, 233, 236, 237, 240, 241, 243, 244, 245, 246, 247, and 249.

In Vivo Rodent Acaricide Test (RAT)

Evaluation of experimental test articles may conducted using a modifiedversion of the assay as described in Gutierrez et al., J. Med. Entomol.43(3): 526-532 (2006). The assay may be modified by using a differenttick species (the reference describes Amblyomma americanum ticks) suchas Dermacentor variabilis ticks. Further, the reference describes usingtopical administration, but oral administration may be used. Briefly,experimental test articles are formulated in a solution of polyethyleneglycol-300, propylene glycol and water to the desired concentration,typically 1-25 mg/ml, depending on solubility and desired point dose.Tick containment units (comprised of a baby nipple, ventilated screw captop and reinforcing rubber washer) are attached to the dorsum of adultSprague-Dawley rats. After attachment of containment units,approximately 10 unfed nymphal stage American dog ticks (Dermacentorvariabilis) are placed inside of each containment unit. Approximately 24hours after infestation, test article formulations are administered torats via oral gavage. Negative control rats receive polyethyleneglycol-300, propylene glycol and water alone. Depending on compoundavailability, a minimum of three (3) and a maximum of five (5) rats areutilized per treatment group. Forty-eight (48) hours post-treatment,containment units are removed and live and dead ticks were counted. Livetick counts are transformed using the natural logarithm transformationplus one (Ln count+1); addition of one to each count serve to adjust forcounts that were zero. Geometric mean (GM) group tick counts areobtained via back-transformation of group mean transformed counts andsubtracting one. The non-treated control group is used for comparison tothe groups receiving experimental test articles for the calculation ofpercent efficacy (% reduction in live tick counts). The efficacy oftreatments is calculated by comparing the geometric mean (GM) number oflive ticks observed on treated rats with the GM number of live tickscounted on the negative control rats, using the following formula:

${\% \mspace{14mu} {Efficacy}} = {\frac{\left( {{{GM}\mspace{14mu} \# \mspace{14mu} {live}{\mspace{11mu} \;}{ticks}\mspace{14mu} {control}} - {{GM}\mspace{14mu} \# \mspace{14mu} {live}\mspace{14mu} {ticks}\mspace{14mu} {treated}}} \right)}{{GM}\mspace{14mu} \# \mspace{14mu} {live}\mspace{14mu} {ticks}\mspace{14mu} {control}} \times 100}$

The following Examples exhibited ≧50% efficacy when tested in this assayat a dose of not more than 25 mpk: 32, 36, 38, 39, 41, 42, 43, 45, 46,47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 87b, 95, 96, 234,235, 240, 241, 243, 244, 245, 246, 247, and 249.

Activity in the above assays demonstrates the compounds of the inventionare useful for controlling ecto- or endoparasite infestations.

The following are embodiments of the invention and are non-limiting.

1. A compound, or a salt thereof, of formula I

wherein A is

n is 0 or 1;

R¹ is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3of the same or different halo atoms;

R² is at each occurrence independently hydrogen, C₁-C₅ alkyl, C₃-C₆cycloalkyl, or C₁-C₅ haloalkyl;

R³ is

p is at each occurrence independently 0 or 1;

R⁴ is C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ cyanoalkyl, C₁-C₅ alkylthio,C₃-C₆ cycloalkyl optionally substituted with hydroxy, halo, or C₁-C₅alkyl: C₃-C₅ cycloheteroalkyl optionally substituted with C₁-C₅ alkyl,C₃-C₆ cycloalkyl, or C₁-C₅ haloalkyl: phenyl, thienyl, pyridinyl, or

wherein one of the carbons in said cycloalkyls, independently, orcycloheteroalkyl may form a carbonyl group, and wherein said phenyl,thienyl, or pyridinyl is optionally substituted with halo or a carbamoylgroup;

R⁵ is hydroxy, —O—(C₁-C₅ alkyl), or

R⁶ is hydrogen, C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ cyanoalkyl, C₁-C₅alkylthio, or C₂-C₅ alkynyl;

or R² and R³ combine to form, with the nitrogen to which they areattached,

Y₁, Y₂, and Y₃ are carbon or nitrogen with at most only one of Y₁, Y₂,and Y₃ being nitrogen, and when Y₁, Y₂, or Y₃ is a carbon, each may besubstituted by C₁-C₅ alkyl;

R⁷ is hydrogen, halo, C₁-C₅ alkyl, or

R⁸ is hydroxy, —O—(C₁-C₅ alkyl), or

R⁹ is C₁-C₅ alkyl,

and

R¹⁰ is hydrogen, C₁-C₅ alkyl, C₁-C₅ haloalkyl, C₁-C₅ cyanoalkyl, C₁-C₅alkylthio, or C₂-C₅ alkynyl.

2. A compound of clause 1 wherein A is

3. A compound according to any of clauses 1-2 wherein R² is hydrogen andn is 1.

4. A compound of according to any of clauses 1-3 wherein R³ is

5. A compound according to any of clauses 1 to 4, or salt thereof, being

-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   N,N-Dimethyl-2-(4-{3-[5-(3,4,5-trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carbonyl}-piperazin-1-yl)-acetamide;-   ({3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carbonyl}-amino)-acetic    acid methyl ester;-   ({3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carbonyl}-amino)-acetic    acid methyl ester;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;-   3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic    acid (1,1-dioxo-thietan-3-yl)-amide;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3-oxocyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic    acid (1,1-dioxo-hexahydro-116-thiopyran-4-yl)-amide;-   3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic    acid [2-oxo-1-(2,2,2-trifluoro-ethyl)-pyrrolidin-3-yl]-amide;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;-   N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;-   N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carb    oxamide;-   N—((R)-2-oxopyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   N-(2-oxo-2-(prop-2-ynylamino)ethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;-   N—((R)-2-oxopyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;-   N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;-   N-(2-oxo-2-(prop-2-ynylamino)ethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;-   N-(2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;-   N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(ethylamino)-2-oxoethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((tetrahydrofuran-2-yl)methyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(methylthio)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3-hydroxycyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(5-fluoropyridin-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(tetrahydro-2H-pyran-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(thietan-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   N-(1-cyclopropyl-2-oxopyrrolidin-3-yl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   N-(2-oxo-2-(prop-2-ynylamino)ethyl)-3-(5-(3,4,5-trichlorothiophen-2-yl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic    acid (1,1-dioxo-hexahydro-thiopyran-4-yl)-amide;-   N-(2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   N-(tetrahydro-2H-pyran-4-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   N-(1-cyclopropyl-2-oxopyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic    acid (1,1-dioxo-thietan-3-yl)-amide;-   3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoro    methyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic    acid (1,1-dioxo-hexahydro-thiopyran-4-yl)-amide;-   3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(4-oxocyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   N-(1-cyclopropyl-2-oxopyrrolidin-3-yl)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(4-oxocyclohexyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;-   3-((R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-((S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   N-(4-carbamoylphenyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic    acid (3-carbamoyl-thiophen-2-yl)-amide;-   2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamido)acetic    acid;-   ({3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carbonyl}-amino)-acetic    acid;-   N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide;    or-   N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,4,5-trichlorothiophen-2-yl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide.

6. A compound of clause 1 wherein A is

7. A compound of clause 1 or 6 wherein Y₁ is nitrogen.

8. A compound according to any of clauses 1, 6, or 7, wherein R⁷ is

9. A compound according to any of clauses 6-8, or salt thereof, being

-   3-(4-chlorobenzo[b]thiophen-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;-   2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-thieno[2,3-c]pyridine;-   5-Bromo-2-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-thieno[2,3-b]pyridine;-   2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-thieno[2,3-b]pyridine;-   3-(benzo[b]thiophen-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoro    methyl)-4,5-dihydroisoxazole;-   3-(benzo[d]thiazol-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;-   5-(3,5-dichlorophenyl)-3-(3-methylbenzo[b]thiophen-2-yl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;-   5-(3,5-dichlorophenyl)-3-(5-methylbenzo[b]thiophen-2-yl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;-   3-(5-chlorobenzo[b]thiophen-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;-   methyl    2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thieno[2,3-b]pyridine-5-carboxylate;-   2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-thieno[2,3-b]pyridine-5-carboxylic    acid;-   2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)thieno[2,3-b]pyridine-5-carboxamide;    or-   2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)thieno[2,3-b]pyridine-5-carboxamide.-   10. A compound, or salt thereof, being-   (S)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;-   3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic    acid [(2,2-difluoro-ethylcarbamoyl)-methyl]-amide;-   (S)-3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic    acid [(2,2-difluoro-ethylcarbamoyl)-methyl]-amid);-   3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic    acid [(2-fluoro-ethylcarbamoyl)-methyl]-amide;-   (S)-3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic    acid [(2-fluoro-ethylcarbamoyl)-methyl]-amide;-   3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;    or-   (S)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide.

11. A formulation comprising a compound or salt of any of clauses 1-10and one or more acceptable carriers.

12. The formulation of clause 11 wherein it further comprises at leastone additional active ingredient.

13. The formulation of clause 11 or clause 12 wherein it is a humanpharmaceutical formulation.

14. The formulation of clause 11 or clause 12 wherein it is a veterinarypharmaceutical formulation.

15. A method of controlling a parasite infestation in or on an animal inneed thereof comprising administering an effective amount of a compoundor salt of any of clauses 1-10 to said animal.

16. The method of clause 15 wherein at least one other active ingredientis administered to said animal.

17. The method of clause 15 or clause 16 wherein said animal is a human.

18. The method of clause 15 or clause 16 wherein said animal is acompanion animal.

19. The method of clause 17 or clause 18 wherein said companion animalis a dog or cat.

20. The method of according to any of clauses 15-19 wherein saidparasite is a tick.

21. The method of clause 15 wherein said animal is a livestock animal.

22. A method for preventing or treating diseases transmitted throughparasites comprising administering an effective amount of a compound ofany of clauses 1-10 to an animal in need thereof

23. The method of clause 22 wherein at least one other active ingredientis administered to said animal.

24. The method of clause 22 or clause 23 wherein said animal is a human.

25. The method of clause 22 wherein said animal is a companion animal.

26. The method of clause 25 wherein said companion animal is a dog orcat.

27. The method according to any of clauses 22-26 wherein said parasiteis a tick.

28. The method of clause 22 or clause 23 wherein said animal is alivestock animal.

29. A method for controlling parasites, characterized in that a compoundof any of clauses 1-10 is allowed to act on the pests or their habitat,or both.

30. The method of clause 29 wherein the compound is placed on a plant oran animal.

31. Use of compounds or salts thereof of any of clauses 1-10 forcontrolling parasites.

32. A compound or salt according to any of clauses 1-10 for use intherapy.

33. A compound or salt according to any of clauses 1-10 for use incontrolling an ectoparasite infestation.

34. A compound, or salt thereof, of Formula II

wherein n is 0 or 1;

R¹ is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3of the same or different halo atoms; and

R¹¹ is hydroxy, —O—(C₁-C₄ alkyl), or a halo atom.

35. The compound of 34 wherein R¹ is phenyl substituted with 2 or 3 ofthe same or different halo atoms.

36. The compound according to clauses 34 or 35 wherein R¹¹ is hydroxy.

37. The compound according to any of clauses 34-36 wherein it is

-   3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic    acid methyl ester;-   3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic    acid methyl ester;-   3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic    acid methyl ester-   3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic    acid methyl ester;-   3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic    acid methyl ester;-   3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic    acid methyl ester;-   3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic    acid methyl ester;-   3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic    acid;-   3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic    acid;-   3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic    acid;-   3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic    acid;-   3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic    acid;-   3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic    acid;-   3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic    acid;-   3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carbonyl    chloride; or-   3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carbonyl    chloride.

38. A compound according to clause 34 wherein it is3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid.

39. A compound according to clause 34 wherein it is3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylicacid.

40. A compound according to clause 34 wherein it is3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylicacid.

41. A compound according to clause 34 wherein it is3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylicacid.

42. A process for preparing a compound according to clauses 1-5 or 10,comprising synthetically modifying a compound according to any ofclauses 34-41.

43. The process of clause 42 wherein a compound according to any ofclauses 34-41 is reacted with a compound of the formula

1.-43. (canceled)
 44. A compound, or a salt thereof, of formula I

wherein A is

n is 0 or 1; R¹ is phenyl substituted with 2 or 3 of the same ordifferent halo atoms; R² is, at each occurrence, hydrogen; R³ is

p is, at each occurrence, independently 0 or 1; R⁴ is

R⁵ is

and R⁶ is hydrogen, C₁-C₅ haloalkyl, C₁-C₅ cyanoalkyl, or C₂-C₅ alkynyl.45. The compound of claim 44, or salt thereof, wherein R¹ is phenylsubstituted 3 times with the same or different of chloro and fluoro; nis 0; R³ is —CH₂—R⁴; R⁴ is —C(O)—R⁵; and R⁶ is difluoroethyl,cyanomethyl, or ethylmethyl.
 46. The compound of claim 45 or saltthereof, wherein R¹ is


47. The compound of claim 46 or salt thereof, wherein R³ is


48. The compound of claim 46 or salt thereof, wherein R³ is


49. The compound of claim 46 or salt thereof, wherein R³ is


50. The compound of claim 44, or salt thereof, being3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide.51. The compound of claim 44, or salt thereof, being(S)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide.52. A formulation comprising a compound of claim 44, or a salt thereof,and one or more acceptable carriers.
 53. A formulation comprising acompound of claim 45, or a salt thereof, and one or more acceptablecarriers.
 54. The formulation of claim 53, further comprising anadditional active ingredient.
 55. The formulation of claim 54, whereinthe formulation is an injectable formulation.
 56. A formulationcomprising a compound of claim 47, or a salt thereof, and one or moreacceptable carriers.
 57. The formulation of claim 56 further comprisingan additional active ingredient.
 58. The formulation of claim 57,wherein the formulation is an injectable formulation.
 59. A formulationcomprising a compound of claim 49, or a salt thereof, and one or moreacceptable carriers.
 60. The formulation of claim 59, further comprisingan additional active ingredient.
 61. The formulation of claim 60,wherein the formulation is an injectable formulation.
 62. A formulationcomprising a compound of claim 51, or a salt thereof, and one or moreacceptable carriers.
 63. The formulation of claim 62, further comprisingan additional active ingredient.
 64. The formulation of claim 63,wherein the formulation is an injectable formulation.
 65. A method ofcontrolling a parasite infestation in or on a non-human mammal in needthereof comprising administering an effective amount of a compound ofclaim 44, or salt thereof, to said animal.
 66. The method of claim 65,wherein said non-human mammal is a dog or cat, and said parasite is aflea or tick.
 67. The method of claim 66, wherein the administering isparenteral administration.
 68. A method of controlling a parasiteinfestation in or on a non-human mammal in need thereof comprisingadministering an effective amount of a compound of claim 45, or saltthereof, to said animal.
 69. The method of claim 68, wherein saidnon-human mammal is a dog or cat, and said parasite is a flea or tick.70. The method of claim 69, wherein the administering is parenteraladministration.
 71. A method of controlling a parasite infestation in oron a non-human mammal in need thereof comprising administering aneffective amount of a compound of claim 47, or salt thereof, to saidanimal.
 72. The method of claim 71, wherein said non-human mammal is adog or cat, and said parasite is a flea or tick.
 73. The method of claim72, wherein the administering is parenteral administration.
 74. A methodof controlling a parasite infestation in or on a non-human mammal inneed thereof comprising administering an effective amount of a compoundof claim 49, or salt thereof, to said animal.
 75. The method of claim74, wherein said non-human mammal is a dog or cat, and said parasite isa flea or tick.
 76. The method of claim 75, wherein the administering isparenteral administration.
 77. A method of controlling a parasiteinfestation in or on a non-human mammal in need thereof comprisingadministering an effective amount of a compound of claim 51, or saltthereof, to said animal.
 78. The method of claim 77, wherein saidnon-human mammal is a dog or cat, and said parasite is a flea or tick.79. The method of claim 78, wherein the administering is parenteraladministration.